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1
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Xiao X, Wang QW, Zhou ZY, Wang LS, Huang P. Precision treatment for human epidermal growth factor receptor 2-amplified advanced rectal cancer: A case report. World J Gastrointest Oncol 2025; 17:102690. [DOI: 10.4251/wjgo.v17.i4.102690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/23/2025] [Accepted: 02/17/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer, some patients develop resistance to these treatments. Human epidermal growth factor receptor 2 (HER2) is overexpressed in a subset of patients with colorectal cancer and has been established as a therapeutic target.
CASE SUMMARY This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors (ICIs) in combination with pyrotinib. The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.
CONCLUSION ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer. Chemotherapy following disease progression could enhance efficacy synergistically.
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Affiliation(s)
- Xia Xiao
- Department of Oncology, Wuxi No. 2 People’s Hospital, Jiangnan University Medical Center, Wuxi 214002, Jiangsu Province, China
| | - Qing-Wen Wang
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Zheng-Yang Zhou
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Lei-Sheng Wang
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Pei Huang
- Department of Oncology, Wuxi No. 2 People’s Hospital, Jiangnan University Medical Center, Wuxi 214002, Jiangsu Province, China
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2
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Tang WW, Battistone B, Bauer KM, Weis AM, Barba C, Fadlullah MZH, Ghazaryan A, Tran VB, Lee SH, Agir ZB, Nelson MC, Victor ES, Thibeaux A, Hernandez C, Tantalla J, Tan AC, Rao D, Williams M, Drummond MJ, Beswick EJ, Round JL, Ekiz HA, Voth WP, O'Connell RM. A microRNA-regulated transcriptional state defines intratumoral CD8 + T cells that respond to immunotherapy. Cell Rep 2025; 44:115301. [PMID: 39951377 PMCID: PMC11924119 DOI: 10.1016/j.celrep.2025.115301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 11/24/2024] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
The rising incidence of advanced-stage colorectal cancer (CRC) and poor survival outcomes necessitate new and effective therapies. Immune checkpoint inhibitors (ICIs), specifically anti-PD-1 therapy, show promise, yet clinical determinants of a positive response are suboptimal. Here, we identify microRNA-155 (miR-155) as necessary for CD8+ T cell-infiltrated tumors through an unbiased in vivo CRISPR-Cas9 screen identifying functional tumor antigen-specific CD8+ T cell-expressed microRNAs. T cell miR-155 is required for anti-PD-1 responses and for a vital intratumor CD8+ T cell differentiation cascade by repressing Ship-1, inhibiting Tcf-1 and stemness, and subsequently enhancing Cxcr6 expression, anti-tumor immunity, and effector functions. Based on an underlying miR-155-dependent CD8+ T cell transcriptional profile, we identify a gene signature that predicts ICI responses across 12 diverse cancers. Together, our findings support a model whereby miR-155 serves as a central regulator of CD8+ T cell-dependent cancer immunity and ICI responses that may be leveraged for future therapeutics.
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Affiliation(s)
- William W Tang
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Ben Battistone
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Kaylyn M Bauer
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Allison M Weis
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Cindy Barba
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Muhammad Zaki Hidayatullah Fadlullah
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Arevik Ghazaryan
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Van B Tran
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Soh-Hyun Lee
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Z Busra Agir
- Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey
| | - Morgan C Nelson
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Emmanuel Stephen Victor
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Amber Thibeaux
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Colton Hernandez
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Jacob Tantalla
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Aik C Tan
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Dinesh Rao
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Matthew Williams
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Micah J Drummond
- Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, UT 84108, USA
| | - Ellen J Beswick
- Division of Digestive Disease and Nutrition, Department of Internal Medicine, University of Kentucky, Lexington, KY 40508, USA
| | - June L Round
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - H Atakan Ekiz
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Warren P Voth
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Ryan M O'Connell
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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Nishiki H, Ura H, Togi S, Hatanaka H, Fujita H, Takamura H, Niida Y. Integrated Analysis of Somatic DNA Variants and DNA Methylation of Tumor Suppressor Genes in Colorectal Cancer. Int J Mol Sci 2025; 26:1642. [PMID: 40004106 PMCID: PMC11855003 DOI: 10.3390/ijms26041642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/03/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
DNA methylation of tumor suppressor genes in cancer is known to be a mechanism for silencing gene expression, but much remains unknown about its extent and relationship to somatic variants at the DNA sequence level. In this study, we comprehensively analyzed DNA methylation and somatic variants of all gene regions across the genome of the major tumor suppressor genes, APC, TP53, SMAD4, and mismatch repair genes in colorectal cancer using a novel next-generation sequencing-based analysis method. The Targeted Methyl Landscape (TML) shows that DNA hypermethylation patterns of these tumor suppressor genes in colorectal cancer are more complex and widespread than previously thought. Extremely high levels of DNA methylation were observed in relatively long regions around exon 1A of APC and exon 1 and surrounding region of MLH1. DNA hypermethylation occurred whether or not somatic DNA variants were present in the tumor. Even in tumors where the loss of heterozygosity has been demonstrated by somatic variants alone, additional methylation of the same gene can occur. Our data demonstrate that somatic variants and hypermethylation of these tumor suppressor genes were considered independent, parallel events, not exclusive of each other or having one event affecting the other.
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Affiliation(s)
- Hisashi Nishiki
- General and Digestive Surgery, Kanazawa Medical University, Uchinada 920-0293, Japan; (H.N.); (H.F.); (H.T.)
| | - Hiroki Ura
- Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Japan (S.T.)
- Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
| | - Sumihito Togi
- Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Japan (S.T.)
- Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
| | - Hisayo Hatanaka
- Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Japan (S.T.)
| | - Hideto Fujita
- General and Digestive Surgery, Kanazawa Medical University, Uchinada 920-0293, Japan; (H.N.); (H.F.); (H.T.)
| | - Hiroyuki Takamura
- General and Digestive Surgery, Kanazawa Medical University, Uchinada 920-0293, Japan; (H.N.); (H.F.); (H.T.)
| | - Yo Niida
- Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Japan (S.T.)
- Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
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Jiang Y, Liu Y, Huang H, Zhao T, Zhao Z, Gao Y. Effect of RAS mutations and related immune characteristics on the prognosis of patients with MSI-H/dMMR colorectal cancer. Cancer Immunol Immunother 2025; 74:78. [PMID: 39891700 PMCID: PMC11787098 DOI: 10.1007/s00262-024-03926-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/16/2024] [Indexed: 02/03/2025]
Abstract
PURPOSE Microsatellite high instability/deficient mismatch repair (MSI-H/dMMR) colorectal cancer (CRC) has an active tumor microenvironment, rendering it more sensitive to immune checkpoint inhibitors. Given that studies involving patients with MSI-H colorectal cancer with RAS mutations are scarce, we explored the effect of RAS mutations on the TME in patients with MSI-H/dMMR cancer and identified potential prognostic factors. METHODS Seventy-five patients diagnosed with MSI-H/dMMR colorectal cancer were retrospectively enrolled and divided into RAS-mutant and -wild-type groups. The expression levels of CD11c+ dendritic cells, CD4+ T cells, CD8+ T cells, and regulatory T cell (Treg) markers were detected, and prognostic factors were analyzed. RESULTS RAS-mutant MSI-H colorectal patients were more likely to have: (1) higher platelet values; (2) shorter disease-free survival (DFS); (3) lower infiltrated numbers of CD11c+ dendritic cells, CD4+ T lymphocytes, and CD8+ T lymphocytes, and higher infiltrated numbers of Foxp3+ Treg cells. In MSI-H/dMMR CRC patients: (1) the high CD11c + , CD4 +, and CD8 + cells infiltration group had longer DFS than the low-infiltration group, and Foxp3 + cells infiltration was not significantly correlated with DFS; (2) the RAS mutation status, number of CD11c+ cells infiltrated, and carbohydrate antigen 19-9 (CA19-9) level were the potential prognostic factors. CONCLUSION RAS mutations in patients with MSI-H/dMMR CRC may reduce the infiltration of CD11c+ dendritic cells, CD4+ T cells, and CD8+ T cells, and increase the infiltration of Foxp3+ Treg cells to affect the tumor microenvironment of patients. RAS gene status, CD11c + cells infiltration, and CA19-9 level were potential prognostic factors for MSI-H/dMMR CRC.
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Affiliation(s)
- Yupeng Jiang
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Yuyao Liu
- Department of Oncology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - Hong Huang
- Guilin Medical University, Guilin, 541000, China
| | - Tiantian Zhao
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Zengyi Zhao
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Yawen Gao
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
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Wang Q, Zhong J, Wang Y, Bao J, Li S, Yang L. Efficacy of Combined PD-1 Inhibitor and Bevacizumab in Unresectable Liver Metastasis of MSI-H Colorectal Cancer: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2025; 26:e946757. [PMID: 39789783 PMCID: PMC11730553 DOI: 10.12659/ajcr.946757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/02/2025] [Accepted: 12/16/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Programmed death 1 (PD-1) inhibitors have demonstrated limited effectiveness in patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC). Recent studies suggest that their efficacy can be enhanced when combined with anti-angiogenic agents. CASE REPORT We present a case of a 25-year-old woman with CRC harboring a KRAS mutation and MSI-H status, along with initially unresectable liver metastases. Despite receiving first-line chemotherapy combined with bevacizumab, her disease progressed. Subsequently, she was treated with a combination of a PD-1 inhibitor and bevacizumab as second-line therapy. This approach resulted in a partial response, ultimately leading to a pathological complete response after resection of the liver metastases. The patient continued with the combination therapy for over a year and showed no serious treatment-related adverse events. Postoperative follow-up imaging confirmed the absence of tumor recurrence or metastasis, and the patient remained in remission. CONCLUSIONS This case highlights the potential of combining immune checkpoint inhibitors with anti-angiogenic agents in treating patients with MSI-H metastatic CRC, particularly those with initially unresectable liver metastases. Although further research is warranted to validate this therapeutic strategy, our findings support the use of this combination as a viable option for achieving pathological complete response and improving outcomes in this patient population. Comprehensive clinical studies are needed to optimize conversion therapy regimens and enhance the likelihood of success in treating patients with MSI-H CRC with advanced disease.
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Affiliation(s)
- Qifan Wang
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
| | - Jie Zhong
- Oncology Center, The Fifth Hospital Affiliated to Wenzhou Medical University & Lishui Central Hospital, Lishui, Zhejiang, PR China
| | - Yi Wang
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
| | - Jun Bao
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
| | - Sheng Li
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
| | - Liu Yang
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
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Liang B, Khan M, Storts H, Zhang EH, Zheng X, Xing X, Claybon H, Wilson J, Li C, Jin N, Fishel R, Miles WO, Wang JJ. Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer. Mol Cancer Ther 2025; 24:131-140. [PMID: 39382075 PMCID: PMC11695182 DOI: 10.1158/1535-7163.mct-24-0289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 08/09/2024] [Accepted: 10/04/2024] [Indexed: 10/10/2024]
Abstract
Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.
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Affiliation(s)
- Beiyuan Liang
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Misbah Khan
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Hayden Storts
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Evan H. Zhang
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Xinru Zheng
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Xuanxuan Xing
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Hazel Claybon
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Jenna Wilson
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Chunjie Li
- Division of Medical Oncology, Department of Internal Medicine, James Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210, USA
| | - Ning Jin
- Division of Medical Oncology, Department of Internal Medicine, James Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210, USA
| | - Richard Fishel
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Wayne O. Miles
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Jing J. Wang
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio 43210, USA
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Qu F, Wu S, Yu W. Progress of Immune Checkpoint Inhibitors Therapy for pMMR/MSS Metastatic Colorectal Cancer. Onco Targets Ther 2024; 17:1223-1253. [PMID: 39735789 PMCID: PMC11681808 DOI: 10.2147/ott.s500281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 12/31/2024] Open
Abstract
Immunotherapy is one of the research hotspots in colorectal cancer field in recent years. The colorectal cancer patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) are the primary beneficiaries of immunotherapy. However, the vast majority of colorectal cancers are mismatch repair proficient (pMMR) or microsatellite stability (MSS), and their immune microenvironment is characterized by "cold tumors" that are generally insensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). Studies have shown that some pMMR/MSS colorectal cancer patients regulate the immune microenvironment by combining other treatments, such as multi-target tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, chemotherapy, radiotherapy, anti-epithelial growth factor receptor (EGFR) monoclonal antibodies, and mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and oncolytic viruses, etc. to transform "cold tumor" into "hot tumor", thereby improving the response to immunotherapy. In addition, screening for potential prognostic biomarkers can also enrich the population benefiting from immunotherapy for microsatellite stable colorectal cancer. Therefore, in pMMR or MSS metastatic colorectal cancer (mCRC), the optimization of immunotherapy regimens and the search for effective efficacy prediction biomarkers are currently important research directions. In this paper, we review the progress of efficacy of immunotherapy (mainly ICIs) in pMMR /MSS mCRC, challenges and potential markers, in order to provide research ideas for the development of immunotherapy for mCRC.
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Affiliation(s)
- Fanjie Qu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
| | - Shuang Wu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
| | - WeiWei Yu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
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Jiang Q, Yao F, An Y, Lai X, Li X, Yu Z, Yang XD. Novel nanotherapeutics for cancer immunotherapy by albumin nanoparticles functionalized with PD-1 and PD-L1 aptamers. Cancer Nanotechnol 2024; 15:3. [DOI: 10.1186/s12645-023-00239-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 12/12/2023] [Indexed: 01/05/2025] Open
Abstract
Abstract
Background
PD-1/PD-L1 blockade plays a crucial role in cancer immunotherapy. Exploration of new technologies to further enhance the efficacy of PD-1/PD-L1 blockade is therefore of potential medical importance. Nanotherapeutics can accumulate in tumor tissues due to enhanced permeability and retention (EPR) effects. In this study, a novel nanotherapeutic for cancer immunotherapy was implemented with albumin nanoparticles functionalized by both PD-1 and PD-L1 aptamers.
Results
Albumin nanoparticles (NP) were functionalized with either PD-1 aptamers (PD1-NP), PD-L1 aptamers (PDL1-NP), or both types of aptamers (PD1-NP-PDL1). Average sizes of PD1-NP, PDL1-NP, and PD1-NP-PDL1 were 141.8 nm, 141.8 nm, and 164.2 nm, respectively. PD1-NP had good affinity for activated T cells that expresses PD-1. Similarly, PDL1-NP could bind with MDA-MB-231 or CT26 tumor cells that express PD-L1. Moreover, the bispecific PD1-NP-PDL1 could bind with both the activated T cells and the PD-L1-expressing tumor cells, and tether the two type of cells together. Functionally, aptamer-modified nanoparticles exhibited stronger immune-stimulating effects vs. free aptamers. Specifically, PD1-NP or PDL1-NP induced stronger lymphocyte-mediated cytotoxicity against PD-L1-expressing tumor cells in vitro vs. free PD-1 or PD-L1 aptamers. Animal studies also showed that PD1-NP or PDL1-NP significantly improved antitumor efficacy against CT26 colon cancer in vivo vs. free PD-1 or PD-L1 aptamers. Importantly, the bispecific PD1-NP-PDL1 further boosted the in vivo antitumor efficacy compared with PD1-NP or PDL1-NP, without raising systemic toxicity.
Conclusion
The results suggest that the bispecific PD1-NP-PDL1 is a promising nanotherapeutic to improve the efficacy of PD-1/PD-L1 blockade, and may have application potential in colon cancer treatment.
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Gong X, Liu C, Tang H, Wu S, Yang Q. Application and research progress of synthetic lethality in the development of anticancer therapeutic drugs. Front Oncol 2024; 14:1460412. [PMID: 39655075 PMCID: PMC11625670 DOI: 10.3389/fonc.2024.1460412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 10/31/2024] [Indexed: 12/12/2024] Open
Abstract
With the tremendous success of the PARP inhibitor olaparib in clinical practice, synthetic lethality has become an important field for the discovery and development of anticancer drugs. More and more synthetic lethality targets have been discovered with the rapid development of biotechnology in recent years. Currently, many drug candidates that were designed and developed on the basis of the concept of synthetic lethality have entered clinical trials. Taking representative synthetic lethal targets Poly ADP-ribose polymerase 1 (PARP1), Werner syndrome helicase (WRN) and protein arginine methyltransferase 5 (PRMT5) as examples, this article briefly discusses the application and research progress of synthetic lethality in the development of anticancer drugs.
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Affiliation(s)
| | | | | | | | - Qingyun Yang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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10
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Guo Y, Xie F, Liu X, Ke S, Chen J, Zhao Y, Li N, Wang Z, Yi G, Shen Y, Li D, Zhu C, Zhang Z, Zhao G, Lu H, Li B, Zhao W. Blockade of TNF-α/TNFR2 signalling suppresses colorectal cancer and enhances the efficacy of anti-PD1 immunotherapy by decreasing CCR8+T regulatory cells. J Mol Cell Biol 2024; 16:mjad067. [PMID: 37935468 PMCID: PMC11587560 DOI: 10.1093/jmcb/mjad067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 05/05/2023] [Accepted: 11/02/2023] [Indexed: 11/09/2023] Open
Abstract
The enrichment of regulatory T cells (Tregs) in the tumour microenvironment (TME) has been recognized as one of the major factors in the initiation and development of resistance to immune checkpoint inhibitors. C-C motif chemokine receptor 8 (CCR8), a marker of activated suppressive Tregs, has a significant impact on the functions of Tregs in the TME. However, the regulatory mechanism of CCR8 in Tregs remains unclear. Here, we revealed that a high level of TNF-α in the colorectal cancer (CRC) microenvironment upregulated CCR8 expression in Tregs via the TNFR2/NF-κB signalling pathway and the FOXP3 transcription factor. Furthermore, in both anti-programmed cell death protein 1 (anti-PD1)-responsive and anti-PD1-unresponsive tumour models, PD1 blockade induced CCR8+ Treg infiltration. In both models, Tnfr2 depletion or TNFR2 blockade suppressed tumour progression by reducing CCR8+ Treg infiltration and thus augmented the efficacy of anti-PD1 therapy. Finally, we identified that TNFR2+CCR8+ Tregs but not total Tregs were positively correlated with adverse prognosis in patients with CRC and gastric cancer. Our work reveals the regulatory mechanisms of CCR8 in Tregs and identifies TNFR2 as a promising target for immunotherapy.
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Affiliation(s)
- Yixian Guo
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Feng Xie
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xu Liu
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shouyu Ke
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jieqiong Chen
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yi Zhao
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ning Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine Shanghai 200025, China
| | - Zeyu Wang
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Gang Yi
- Biotheus Inc., Zhuhai 519080, China
| | - Yanying Shen
- Department of Pathology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Dan Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chunchao Zhu
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zizhen Zhang
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Gang Zhao
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hong Lu
- GI Division, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Bin Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wenyi Zhao
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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11
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Ibruli O, Rose F, Beleggia F, Schmitt A, Cartolano M, Fernandez LT, Saggau J, Bonasera D, Kiljan M, Gozum G, Lichius L, Cai J, Niu LN, Caiaffa MI, Herter JM, Walczak H, Liccardi G, Grüll H, Büttner R, Bosco G, George J, Thomas RK, Bozek K, Reinhardt HC, Herter-Sprie GS. A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade. J Cancer Res Clin Oncol 2024; 150:496. [PMID: 39542886 PMCID: PMC11564195 DOI: 10.1007/s00432-024-05942-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 09/04/2024] [Indexed: 11/17/2024]
Abstract
PURPOSE Small cell lung cancer (SCLC) has an extremely poor prognosis. Despite high initial response rates to chemotherapy and modest survival improvements with the addition of immune checkpoint inhibitors (ICI), almost all patients experience relapse and fatal outcomes. Recent genomic insights uncovered extensive molecular heterogeneity in addition to the almost uniform loss of RB1 and TRP53. Additionally, defective DNA mismatch repair (MMR) has recently been described in some SCLC cases. Here, we generated a novel SCLC mouse model capturing MMR deficiency and assessed immunotherapy responses. METHODS We developed an MMR-deficient genetically engineered mouse model (GEMM) of SCLC by introducing a conditional Msh2 gene, crucial for maintaining MMR integrity, into the standard Rb1fl/fl;Trp53fl/fl (RP) model. Genomic characteristics and preclinical therapy responses were evaluated by focusing on overall survival and whole exome sequencing (WES) analyses. RESULTS MMR-defective SCLC tumors (Rb1fl/fl;Trp53fl/fl;Msh2fl/fl (RPM)) developed later than tumors in MMR-proficient mice. However, the time from tumor manifestation to death of the affected animals was substantially shortened (median survival 55 days in RP vs. 46.5 days in RPM), indicating increased aggressiveness of MMR-defective tumors. RPM tumors exhibited MMR deficiency, high tumor mutational burden (TMB), and an elevated load of candidate neoantigens, compared to RP lesions (p = 0.0106), suggesting increased immunogenicity. Importantly, the overall survival of RPM animals was significantly improved when exposed to ICI. CONCLUSION We propose a novel RPM mouse model as a suitable system to mimic MMR-defective SCLC and tumors with high TMB. We provide in vivo evidence that Msh2 deficiency enhances ICI sensitivity. These findings could contribute to stratifying SCLC patients to immunotherapy, thereby improving treatment outcomes.
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Affiliation(s)
- Olta Ibruli
- Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - France Rose
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute for Biomedical Informatics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Filippo Beleggia
- Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Anna Schmitt
- Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute of Virology, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Maria Cartolano
- Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Lucia Torres Fernandez
- Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Julia Saggau
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute of Biochemistry I, Center for Biochemistry, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Debora Bonasera
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute of Biochemistry I, Center for Biochemistry, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Martha Kiljan
- Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Gokcen Gozum
- Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Luca Lichius
- Department II of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jiali Cai
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of Radiation Oncology and Cyberknife Center, Faculty of Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Li-Na Niu
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of Radiation Oncology and Cyberknife Center, Faculty of Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Manoela Iannicelli Caiaffa
- Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jan M Herter
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of Radiation Oncology and Cyberknife Center, Faculty of Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany
- Department of Radiation Oncology, MVZ Prof. Dr. Uhlenbrock und Partner, Gesundheitscampus Josephs-Hospital, Warendorf, Germany
| | - Henning Walczak
- Institute of Biochemistry I, Center for Biochemistry, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Center for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK
| | - Gianmaria Liccardi
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute of Biochemistry I, Center for Biochemistry, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Holger Grüll
- Institute for Diagnostic and Interventional Radiology, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Reinhard Büttner
- Institute of Pathology, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Graziella Bosco
- Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Julie George
- Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of Otorhinolaryngology, Faculty of Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Roman K Thomas
- Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute of Pathology, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Kasia Bozek
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Institute for Biomedical Informatics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hans Christian Reinhardt
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen, Essen, Germany
- DKTK Partner Site Essen/Düsseldorf, University Hospital Essen, Essen, Germany
- Center for Molecular Biotechnology, University Hospital Essen, Essen, Germany
| | - Grit S Herter-Sprie
- Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
- Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
- Department of Medical Oncology, Fachklinik Hornheide, Münster, Germany.
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12
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Li Y, Tan L, Chen N, Liu X, Liang F, Yao Y, Zhang X, Wu A. Neoadjuvant Immunotherapy Alone for Patients With Locally Advanced and Resectable Metastatic Colorectal Cancer of dMMR/MSI-H Status. Dis Colon Rectum 2024; 67:1413-1422. [PMID: 39260435 DOI: 10.1097/dcr.0000000000003290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
BACKGROUND The use of programmed death-1 blockade has a significant therapeutic effect in patients with mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. However, data on preoperative single-agent programmed death-1 blockade are rare. OBJECTIVE This study aims to evaluate the effectiveness and safety of preoperative programmed death-1 blockade as a conversion strategy in patients with locally advanced and resectable metastatic mismatch repair-deficient/microsatellite instability-high colorectal cancer. DESIGN This is a retrospective observational study. SETTINGS This study was conducted at a high-volume tertiary referral cancer center in China. PATIENTS Twenty-four patients of consecutive cases since 2020 to 2022 with mismatch repair-deficient/microsatellite instability-high colorectal cancer who received preoperative single-agent programmed death-1 blockade were retrospectively reviewed. These patients had either bulking tumors scheduled for multivisceral resection, a strong desire for organ preservation, or potentially resectable metastatic lesions. MAIN OUTCOME MEASURES Pathological complete response, clinical complete response, toxicity, R0 resection rate, and complications were evaluated. RESULTS Patients tolerated preoperative immunotherapy well. The R0 resection rate was 95.2%, and the pathological complete response rate was 47.6%. Three patients (12.5%) were evaluated as having a clinical complete response and then underwent "watch and wait." One-half of the patients with cT4b were spared multivisceral resection, whereas 60% (3/5) achieved pathological complete response. All 3 patients with liver metastases obtained complete response of all liver lesions after programmed death-1 blockade treatment. Grade III postoperative complications occurred in 2 patients. LIMITATIONS The limitations of this study are as follows: retrospective study, small sample size, and short follow-up. CONCLUSIONS Preoperative anti-programmed death-1 therapy alone as a conversion strategy in initially resected difficult mismatch repair-deficient/microsatellite instability-high colorectal cancer can achieve a high tumor complete response. The use of immunopreoperative therapy in patients with T4b colon cancer or low rectal cancer can reduce multivisceral resection and achieve high organ function preservation. See the Video Abstract . INMUNOTERAPIA NEOADYUVANTE SOLA PARA PACIENTES CON CNCER COLORRECTAL LOCALMENTE AVANZADO Y METASTSICO RESECABLE CON ESTADO DMMR/MSIH ANTECEDENTES:El uso del bloqueo de muerte programada-1 tiene un efecto terapéutico significativo en pacientes con cáncer colorrectal metastásico deficiente en reparación de desajustes/inestabilidad de microsatélites-alta (dMMR/MSI-H). Sin embargo, los datos sobre el bloqueo preoperatorio de muerte programada-1 con un solo agente son escasos.OBJETIVO:Este estudio tiene como objetivo evaluar la eficacia y seguridad del bloqueo preoperatorio de muerte programada-1 como estrategia de conversión en pacientes con cáncer colorrectal localmente avanzado y metastásico resecable con dMMR/MSI-H.DISEÑO:Este es un estudio observacional retrospectivo.ESCENARIO:Este estudio se realizó en un centro oncológico terciario de referencia de gran volumen en China.PACIENTES:Se revisaron retrospectivamente veinticuatro pacientes de casos consecutivos desde 2020-2022 con cáncer colorrectal y dMMR/MSI-H que recibieron bloqueo preoperatorio de muerte programada-1 con un solo agente. Estos pacientes tenían un tumor voluminoso programado para resección multivisceral, un fuerte deseo de preservación del órgano o lesiones metastásicas potencialmente resecables.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron la respuesta patológica completa, la respuesta clínica completa, la toxicidad, la tasa de resección R0 y las complicaciones.RESULTADOS:Los pacientes toleraron bien la inmunoterapia preoperatoria. La tasa de resección R0 fue del 95,2% y la tasa de respuesta patológica completa fue del 47,6%. Tres pacientes (12,5%) fueron evaluados como respuesta clínica completa y luego sometidos a "observar y esperar". La mitad de los pacientes cT4b se salvaron de la resección multivisceral, mientras que el 60% (3/5) lograron una respuesta patológica completa. Los tres pacientes con metástasis hepáticas obtuvieron respuesta completa de todas las lesiones hepáticas después del tratamiento de bloqueo de muerte programada-1. En dos pacientes se produjeron complicaciones postoperatorias de grado III.LIMITACIONES:Las limitaciones de este estudio son las siguientes: estudio retrospectivo, tamaño de muestra pequeño y seguimiento corto.CONCLUSIONES:La terapia preoperatoria anti muerte programada-1 sola como estrategia de conversión en el cáncer colorrectal inicialmente difícil de resecar con dMMR/MSI-H puede lograr una alta respuesta completa tumoral. El uso de terapia inmunopreoperatoria en pacientes con cáncer de colon T4b o cáncer de recto bajo puede reducir la resección multivisceral y lograr una alta preservación de la función del órgano. (Traducción-Dr. Felipe Bellolio ).
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Affiliation(s)
- Yingjie Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital and Institute, Beijing, China
| | - Luxin Tan
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China
| | - Nan Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital and Institute, Beijing, China
| | - Xinzhi Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital and Institute, Beijing, China
| | - Fei Liang
- Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunfeng Yao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital and Institute, Beijing, China
| | - Xiaoyan Zhang
- Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China
| | - Aiwen Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital and Institute, Beijing, China
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13
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Liang B, Xing X, Storts H, Ye Z, Claybon H, Austin R, Ding R, Liu B, Wen H, Miles WO, Fishel R, Wang JJ. Antagonistic roles of cGAS/STING signaling in colorectal cancer chemotherapy. Front Oncol 2024; 14:1441935. [PMID: 39469633 PMCID: PMC11513249 DOI: 10.3389/fonc.2024.1441935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/27/2024] [Indexed: 10/30/2024] Open
Abstract
FOLFOX, composed of 5-FU, oxaliplatin and leucovorin, is a first line chemotherapy regimen for colorectal cancer (CRC) treatment. In this study, we show that 5-FU and oxaliplatin induce DNA damage and activate cGAS/STING signaling leading to enhanced expression of interferon (IFN) β, IFN-stimulated genes and inflammatory cytokines in mouse and human colon cancer cells as well as increased intratumoral CD8+ T cells in mice. Crucially, 5-FU and oxaliplatin increase PD-L1 expression at the mRNA and protein levels, which has been shown to inhibit CD8+ T cell function. Depletion of cGAS, STING, IRF3, or IFNα/β receptor 1 (IFNAR1) abolishes this increase, indicating that 5-FU/oxaliplatin mediated upregulation of PD-L1 expression is dependent on tumor cell intrinsic cGAS/STING signaling. These results imply opposing roles for FOLFOX during cancer treatment. On one hand, 5-FU and oxaliplatin activate the innate immune response to facilitate anti-tumor immunity, and conversely upregulate PD-L1 expression to evade immune surveillance. Analysis of TCGA colon cancer dataset shows a positive correlation between expression of PD-L1 and components of the cGAS/STING pathway, supporting a role for cGAS/STING signaling in upregulating PD-L1 expression in colon cancer patients. Tumor studies in syngeneic immune competent mice demonstrate that the combination of 5-FU/oxaliplatin and anti-PD-1 significantly reduced tumor growth of colon cancer cells compared to 5-FU/oxaliplatin treatment alone. Taken together, our studies have identified a unique pathway leading to chemoresistance and provide a rationale to combine FOLFOX with anti-PD-1/PD-L1 as an effective CRC treatment.
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Affiliation(s)
- Beiyuan Liang
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Xuanxuan Xing
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Hayden Storts
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Zhen Ye
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Hazel Claybon
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Ryan Austin
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Rachel Ding
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Bei Liu
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, James Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
| | - Haitao Wen
- Pelotonia Institute for Immuno-Oncology, James Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
| | - Wayne O. Miles
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Richard Fishel
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| | - Jing J. Wang
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, James Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
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Zhao C, Zhao J, Zhang Y, Zhu Y, Yang Z, Liu S, Tang Q, Yang Y, Wang H, Shu Y, Dong P, Wu X, Gong W. PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2406633. [PMID: 39116343 PMCID: PMC11481411 DOI: 10.1002/advs.202406633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/31/2024] [Indexed: 08/10/2024]
Abstract
Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.
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Affiliation(s)
- Cheng Zhao
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Jing‐wei Zhao
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Yu‐han Zhang
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Yi‐di Zhu
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Zi‐yi Yang
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Shi‐lei Liu
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Qiu‐yi Tang
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Yue Yang
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Hua‐kai Wang
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Yi‐jun Shu
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Ping Dong
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Xiang‐song Wu
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
| | - Wei Gong
- Laboratory of General Surgery and Department of General SurgeryXinhua Hospital affiliated with Shanghai Jiao Tong University School of MedicineNo. 1665 Kongjiang RoadShanghai200092China
- Shanghai Key Laboratory of Biliary Tract Disease ResearchNo. 1665 Kongjiang RoadShanghai200092China
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15
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Su X, Li J, Xu X, Ye Y, Wang C, Pang G, Liu W, Liu A, Zhao C, Hao X. Strategies to enhance the therapeutic efficacy of anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody in cancer therapy. J Transl Med 2024; 22:751. [PMID: 39123227 PMCID: PMC11316358 DOI: 10.1186/s12967-024-05552-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Although immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody) have displayed considerable success in the treatment of malignant tumors, the therapeutic effect is still unsatisfactory for a portion of patients. Therefore, it is imperative to develop strategies to enhance the effect of these ICIs. Increasing evidence strongly suggests that the key to this issue is to transform the tumor immune microenvironment from a state of no or low immune infiltration to a state of high immune infiltration and enhance the tumor cell-killing effect of T cells. Therefore, some combination strategies have been proposed and this review appraise a summary of 39 strategies aiming at enhancing the effectiveness of ICIs, which comprise combining 10 clinical approaches and 29 foundational research strategies. Moreover, this review improves the comprehensive understanding of combination therapy with ICIs and inspires novel ideas for tumor immunotherapy.
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Affiliation(s)
- Xin Su
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Jian Li
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Xiao Xu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Youbao Ye
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Cailiu Wang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Guanglong Pang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Wenxiu Liu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Ang Liu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Changchun Zhao
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Xiangyong Hao
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China.
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16
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Ortega MA, Boaru DL, De Leon-Oliva D, Fraile-Martinez O, García-Montero C, Rios L, Garrido-Gil MJ, Barrena-Blázquez S, Minaya-Bravo AM, Rios-Parra A, Álvarez-Mon M, Jiménez-Álvarez L, López-González L, Guijarro LG, Diaz R, Saez MA. PD-1/PD-L1 axis: implications in immune regulation, cancer progression, and translational applications. J Mol Med (Berl) 2024; 102:987-1000. [PMID: 38935130 DOI: 10.1007/s00109-024-02463-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024]
Abstract
The PD-1/PD-L1 axis is a complex signaling pathway that has an important role in the immune system cells. Programmed cell death protein 1 (PD-1) acts as an immune checkpoint on the T lymphocytes, B lymphocytes, natural killer (NK), macrophages, dendritic cells (DCs), monocytes, and myeloid cells. Its ligand, the programmed cell death 1 ligand (PD-L1), is expressed in the surface of the antigen-presenting cells (APCs). The binding of both promotes the downregulation of the T cell response to ensure the activation to prevent the onset of chronic immune inflammation. This axis in the tumor microenvironment (TME) performs a crucial role in the tumor progression and the escape of the tumor by neutralizing the immune system, the engagement of PD-L1 with PD-1 in the T cell causes dysfunctions, neutralization, and exhaustion, providing the tumor mass production. This review will provide a comprehensive overview of the functions of the PD-1/PD-L1 system in immune function, cancer, and the potential therapeutic implications of the PD-1/PD-L1 pathway for cancer management.
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Affiliation(s)
- Miguel A Ortega
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain.
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain.
- Cancer Registry and Pathology Department, Principe de, Asturias University Hospital, Alcala de Henares, Spain.
| | - Diego Liviu Boaru
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Diego De Leon-Oliva
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Cielo García-Montero
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Laura Rios
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Maria J Garrido-Gil
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Silvestra Barrena-Blázquez
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of Nursing and Physiotherapy, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Ana M Minaya-Bravo
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Antonio Rios-Parra
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Cancer Registry and Pathology Department, Principe de, Asturias University Hospital, Alcala de Henares, Spain
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Immune System Diseases-Rheumatology Service, University Hospital Principe de Asturias, CIBEREHD, 28801, Alcala de Henares, Spain
| | - Laura Jiménez-Álvarez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Laura López-González
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Luis G Guijarro
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Raul Diaz
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain.
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain.
- Surgery Service, University Hospital Principe de Asturias, 28801, Alcala de Henares, Spain.
| | - Miguel A Saez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Pathological Anatomy Service, Central University Hospital of Defence-University of Alcalá (UAH) Madrid, Alcala de Henares, Spain
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Shukla S, Patel H, Chen S, Sun R, Wei L, Chen ZS. Dostarlimab in the treatment of mismatch repair deficient recurrent or advanced endometrial cancer. CANCER PATHOGENESIS AND THERAPY 2024; 2:135-141. [PMID: 39027143 PMCID: PMC11252537 DOI: 10.1016/j.cpt.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 10/05/2023] [Accepted: 10/13/2023] [Indexed: 07/20/2024]
Abstract
Dostarlimab, a programmed death receptor-1 (PD-1)-blocking IgG4 humanized monoclonal antibody, gained accelerated approval from the US Food and Drug Administration (FDA) in April 2021, and received a full approval in February 2023. Dostarlimab was approved for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) that progressed during or after prior treatment who have no other suitable treatment options. Herein, we review the structure-based mechanism of action of dostarlimab and the results of a clinical study (GARNET; NCT02715284) to comprehensively clarify the efficacy and toxicity of the drug. The efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized, multicenter, open-label, multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic therapy. Patients received 500 mg of dostarlimab intravenously every three weeks until they were given four doses. Then, patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable toxicity. The overall response rate, as determined by shrinkage in tumor size, was 41.6% (95% confidence interval [CI]; 34.9, 48.6), with 34.7 months as the median response duration. In conclusion, dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR EC. However, its efficacy in other cancer subtypes, the development of resistance to monotherapy, and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.
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Affiliation(s)
- Siddhant Shukla
- Institute for Biotechnology, St. John's University, New York, New York 11439, United States
| | - Harsh Patel
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, New York 11439, United States
| | - Shuzhen Chen
- School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, China
| | - Rainie Sun
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, New York 11439, United States
- Stuyvesant High School, New York, New York 10282, United States
| | - Liuya Wei
- School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, China
| | - Zhe-Sheng Chen
- Institute for Biotechnology, St. John's University, New York, New York 11439, United States
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, New York 11439, United States
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18
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An TQ, Qiu H, Zhou QB, Zong H, Hu S, Lian YG, Zhao RH. Efficacy comparison of fruquintinib, regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer. World J Gastrointest Oncol 2024; 16:2437-2450. [DOI: 10.4251/wjgo.v16.i6.2437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/20/2024] [Accepted: 04/07/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Regorafenib (R) and fruquintinib (F) are the standard third-line regimens for colorectal cancer (CRC) according to the National Comprehensive Cancer Network guidelines, but both have limited efficacy. Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair (MSS/pMMR) CRC. Due to the lack of studies comparing the efficacy between F, R, F plus programmed death-1 (PD-1) inhibitor, and R plus PD-1 inhibitors (RP), it is still unclear whether the combination therapy is more effective than monotherapy.
AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC (mCRC) patients in clinical practice.
METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital, and 313 MSS/pMMR mCRC patients were finally included.
RESULTS A total of 313 eligible patients were divided into F (n = 70), R (n = 67), F plus PD-1 inhibitor (FP) (n = 95) and RP (n = 81) groups. The key clinical characteristics were well balanced among the groups. The median progression-free survival (PFS) of the F, R, FP, and RP groups was 3.5 months, 3.6 months, 4.9 months, and 3.0 months, respectively. The median overall survival (OS) was 14.6 months, 15.7 months, 16.7 months, and 14.1 months. The FP regimen had an improved disease control rate (DCR) (P = 0.044) and 6-month PFS (P = 0.014) and exhibited a better trend in PFS (P = 0.057) compared with F, and it was also significantly better in PFS than RP (P = 0.030). RP did not confer a significant survival benefit; instead, the R group had a trend toward greater benefit with OS (P = 0.080) compared with RP. No significant differences were observed between the R and F groups in PFS or OS (P > 0.05).
CONCLUSION FP is superior to F in achieving 6-month PFS and DCR, while RP is not better than R. FP has an improved PFS and 6-month PFS compared with RP, but F and R had similar clinical efficacy. Therefore, FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.
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Affiliation(s)
- Tian-Qi An
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Hui Qiu
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing 100000, China
| | - Quan-Bo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Shuang Hu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Yu-Gui Lian
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Rui-Hua Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
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Chen H, Jiang RY, Hua Z, Wang XW, Shi XL, Wang Y, Feng QQ, Luo J, Ning W, Shi YF, Zhang DK, Wang B, Jie JZ, Zhong DR. Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients. World J Gastrointest Oncol 2024; 16:2673-2682. [PMID: 38994136 PMCID: PMC11236251 DOI: 10.4251/wjgo.v16.i6.2673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/23/2024] [Accepted: 04/12/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND RAS, BRAF, and mismatch repair (MMR)/microsatellite instability (MSI) are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer (CRC). However, their characteristics and influencing factors in Chinese patients have not been thoroughly described. AIM To analyze the clinicopathological features of KRAS, NRAS, BRAF, and PIK3CA mutations and the DNA MMR status in CRC. METHODS We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital. MMR proteins were tested using immunohistochemical analysis, and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction. Microsatellite status was determined using an MSI detection kit. Statistical analyses were conducted using SPSS software and logistic regression. RESULTS The KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 44.6%, 3.4%, 3.7%, and 3.9% of CRC patients, respectively. KRAS mutations were more likely to occur in patients with moderate-to-high differentiation. BRAF mutations were more likely to occur in patients with right-sided CRC, poorly differentiated, or no perineural invasion. Deficient MMR (dMMR) was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas. KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 29.6%, 1.1%, 8.1%, and 22.3% of patients with dMMR, respectively. The dMMR was more likely to occur in patients with a family history of CRC, aged < 50 years, right-sided CRC, poorly differentiated histology, no perineural invasion, and with carcinoma in situ, stage I, or stage II tumors. CONCLUSION This study analyzed the molecular profiles of KRAS, NRAS, BRAF, PIK3CA, and MMR/MSI in CRC, identifying key influencing factors, with implications for clinical management of CRC.
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Affiliation(s)
- Huang Chen
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Rui-Ying Jiang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Zhan Hua
- Department of Gastrointestinal Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao-Wei Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao-Li Shi
- Department of Scientific Research, Geneis, Beijing 100012, China
| | - Ye Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Qian-Qian Feng
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jie Luo
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wu Ning
- Department of Gastrointestinal Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yan-Fen Shi
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Da-Kui Zhang
- Department of Gastrointestinal Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Bei Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jian-Zheng Jie
- Department of Gastrointestinal Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Ding-Rong Zhong
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
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20
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Chen H, Jiang RY, Hua Z, Wang XW, Shi XL, Wang Y, Feng QQ, Luo J, Ning W, Shi YF, Zhang DK, Wang B, Jie JZ, Zhong DR. Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients. World J Gastrointest Oncol 2024; 16:2661-2670. [DOI: 10.4251/wjgo.v16.i6.2661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/23/2024] [Accepted: 04/12/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND RAS, BRAF, and mismatch repair (MMR)/microsatellite instability (MSI) are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer (CRC). However, their characteristics and influencing factors in Chinese patients have not been thoroughly described.
AIM To analyze the clinicopathological features of KRAS, NRAS, BRAF, and PIK3CA mutations and the DNA MMR status in CRC.
METHODS We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital. MMR proteins were tested using immunohistochemical analysis, and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction. Microsatellite status was determined using an MSI detection kit. Statistical analyses were conducted using SPSS software and logistic regression.
RESULTS The KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 44.6%, 3.4%, 3.7%, and 3.9% of CRC patients, respectively. KRAS mutations were more likely to occur in patients with moderate-to-high differentiation. BRAF mutations were more likely to occur in patients with right-sided CRC, poorly differentiated, or no perineural invasion. Deficient MMR (dMMR) was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas. KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 29.6%, 1.1%, 8.1%, and 22.3% of patients with dMMR, respectively. The dMMR was more likely to occur in patients with a family history of CRC, aged < 50 years, right-sided CRC, poorly differentiated histology, no perineural invasion, and with carcinoma in situ, stage I, or stage II tumors.
CONCLUSION This study analyzed the molecular profiles of KRAS, NRAS, BRAF, PIK3CA, and MMR/MSI in CRC, identifying key influencing factors, with implications for clinical management of CRC.
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Affiliation(s)
- Huang Chen
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Rui-Ying Jiang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Zhan Hua
- Department of Gastrointestinal Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao-Wei Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao-Li Shi
- Department of Scientific Research, Geneis, Beijing 100012, China
| | - Ye Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Qian-Qian Feng
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jie Luo
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wu Ning
- Department of Gastrointestinal Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yan-Fen Shi
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Da-Kui Zhang
- Department of Gastrointestinal Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Bei Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jian-Zheng Jie
- Department of Gastrointestinal Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Ding-Rong Zhong
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
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21
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An TQ, Qiu H, Zhou QB, Zong H, Hu S, Lian YG, Zhao RH. Efficacy comparison of fruquintinib, regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer. World J Gastrointest Oncol 2024; 16:2449-2462. [PMID: 38994132 PMCID: PMC11236229 DOI: 10.4251/wjgo.v16.i6.2449] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/20/2024] [Accepted: 04/07/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Regorafenib (R) and fruquintinib (F) are the standard third-line regimens for colorectal cancer (CRC) according to the National Comprehensive Cancer Network guidelines, but both have limited efficacy. Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair (MSS/pMMR) CRC. Due to the lack of studies comparing the efficacy between F, R, F plus programmed death-1 (PD-1) inhibitor, and R plus PD-1 inhibitors (RP), it is still unclear whether the combination therapy is more effective than monotherapy. AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC (mCRC) patients in clinical practice. METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital, and 313 MSS/pMMR mCRC patients were finally included. RESULTS A total of 313 eligible patients were divided into F (n = 70), R (n = 67), F plus PD-1 inhibitor (FP) (n = 95) and RP (n = 81) groups. The key clinical characteristics were well balanced among the groups. The median progression-free survival (PFS) of the F, R, FP, and RP groups was 3.5 months, 3.6 months, 4.9 months, and 3.0 months, respectively. The median overall survival (OS) was 14.6 months, 15.7 months, 16.7 months, and 14.1 months. The FP regimen had an improved disease control rate (DCR) (P = 0.044) and 6-month PFS (P = 0.014) and exhibited a better trend in PFS (P = 0.057) compared with F, and it was also significantly better in PFS than RP (P = 0.030). RP did not confer a significant survival benefit; instead, the R group had a trend toward greater benefit with OS (P = 0.080) compared with RP. No significant differences were observed between the R and F groups in PFS or OS (P > 0.05). CONCLUSION FP is superior to F in achieving 6-month PFS and DCR, while RP is not better than R. FP has an improved PFS and 6-month PFS compared with RP, but F and R had similar clinical efficacy. Therefore, FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.
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Affiliation(s)
- Tian-Qi An
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Hui Qiu
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing 100000, China
| | - Quan-Bo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Shuang Hu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Yu-Gui Lian
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Rui-Hua Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
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22
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Du D, Yang Y, Zhang Y, Wang G, Chen L, Guan X, Rasmussen LJ, Liu D. MRE11A: a novel negative regulator of human DNA mismatch repair. Cell Mol Biol Lett 2024; 29:37. [PMID: 38486171 PMCID: PMC10938699 DOI: 10.1186/s11658-024-00547-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 02/08/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND DNA mismatch repair (MMR) is a highly conserved pathway that corrects DNA replication errors, the loss of which is attributed to the development of various types of cancers. Although well characterized, MMR factors remain to be identified. As a 3'-5' exonuclease and endonuclease, meiotic recombination 11 homolog A (MRE11A) is implicated in multiple DNA repair pathways. However, the role of MRE11A in MMR is unclear. METHODS Initially, short-term and long-term survival assays were used to measure the cells' sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Meanwhile, the level of apoptosis was also determined by flow cytometry after MNNG treatment. Western blotting and immunofluorescence assays were used to evaluate the DNA damage within one cell cycle after MNNG treatment. Next, a GFP-heteroduplex repair assay and microsatellite stability test were used to measure the MMR activities in cells. To investigate the mechanisms, western blotting, the GFP-heteroduplex repair assay, and chromatin immunoprecipitation were used. RESULTS We show that knockdown of MRE11A increased the sensitivity of HeLa cells to MNNG treatment, as well as the MNNG-induced DNA damage and apoptosis, implying a potential role of MRE11 in MMR. Moreover, we found that MRE11A was largely recruited to chromatin and negatively regulated the DNA damage signals within the first cell cycle after MNNG treatment. We also showed that knockdown of MRE11A increased, while overexpressing MRE11A decreased, MMR activity in HeLa cells, suggesting that MRE11A negatively regulates MMR activity. Furthermore, we show that recruitment of MRE11A to chromatin requires MLH1 and that MRE11A competes with PMS2 for binding to MLH1. This decreases PMS2 levels in whole cells and on chromatin, and consequently comprises MMR activity. CONCLUSIONS Our findings reveal that MRE11A is a negative regulator of human MMR.
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Affiliation(s)
- Demin Du
- Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yueyan Yang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yuanyuan Zhang
- Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Guanxiong Wang
- Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Liying Chen
- Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xiaowei Guan
- Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Lene Juel Rasmussen
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen, Denmark.
| | - Dekang Liu
- Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Yang H, Xiao X, Zeng L, Zeng H, Zheng Y, Wang J, Li G, Dai W, He Y, Wang S, Peng J, Chen W. Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer. J Transl Med 2024; 22:132. [PMID: 38310289 PMCID: PMC10837874 DOI: 10.1186/s12967-023-04675-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 10/29/2023] [Indexed: 02/05/2024] Open
Abstract
BACKGROUND The current precision medicine relies on biomarkers, which are mainly obtained through next-generation sequencing (NGS). However, this model failed to find effective drugs for most cancer patients. This study tried to combine liquid biopsy with functional drug tests using organoid models to find potential drugs for cancer patients. METHODS Colorectal cancer (CRC) patients were prospectively enrolled and blood samples were collected from patients before the start of treatment. Targeted deep sequencing of cfDNA samples was performed using a 14-gene panel. Gastrointestinal (GI) cancer organoids were established and PI3K and mTOR inhibitors were evaluated on organoid models. RESULTS A total of 195 mutations were detected across 58 cfDNA samples. The most frequently mutated genes were KRAS, TP53, PIK3CA, and BRAF, all of which exhibited higher mutation rates than tissue biopsy. Although 81% of variants had an allele frequency of less than 1%, certain mutations in KRAS, TP53, and SMAD4 had high allele frequencies exceeding 10%. Notably, among the seven patients with high allele frequency mutations, six had metastatic tumors, indicating that a high allele frequency of ctDNA could potentially serve as a biomarker of later-stage cancer. A high rate of PIK3CA mutation (31 out of 67, or 46.3%) was discovered in CRC patients, suggesting possible tumor progression mechanisms and targeted therapy opportunities. To evaluate the value of anti PI3K strategy in GI cancer, different lines of GI cancer organoids were established. The organoids recapitulated the morphologies of the original tumors. Organoids were generally insensitive to PI3K inhibitors. However, CRC-3 and GC-4 showed response to mTOR inhibitor Everolimus, and GC-3 was sensitive to PI3Kδ inhibitor Idelalisib. The CRC organoid with a PIK3CA mutation showed greater sensitivity to the PI3K inhibitor Alpelisib than wildtype organoids, suggesting potential treatment options for the corresponding patients. CONCLUSION Liquid biopsy holds significant promise for improving precision treatment and tumor prognosis in colorectal cancer patients. The combination of biomarker-based drug prediction with organoid-based functional drug sensitivity assay may lead to more effective cancer treatment.
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Affiliation(s)
- Huan Yang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, Guangdong, China
| | - Xing Xiao
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, Guangdong, China
| | - Leli Zeng
- Department of Biobank, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Haiteng Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, Guangdong, China
| | - Yueyuan Zheng
- Clinical Big Data Research Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Jingshu Wang
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Guanghua Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Weigang Dai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, Guangdong, China
- Department of Gastrointestinal Surgery, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Suihai Wang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
| | - Jianjun Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, Guangdong, China.
- Department of Gastrointestinal Surgery, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.
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24
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Tong G, Zhang G, Hu Y, Xu X, Wang Y. Correlation between mismatch repair statuses and the prognosis of stage I-IV colorectal cancer. Front Oncol 2024; 13:1278398. [PMID: 38348120 PMCID: PMC10859923 DOI: 10.3389/fonc.2023.1278398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/27/2023] [Indexed: 02/15/2024] Open
Abstract
Background The role of microsatellite instability (MSI) and prognosis for stage II-III colorectal cancer (CRC) has been described, but the role of MSI in stage I and IV CRC is controversial. Methods A total of 2,540 CRC patients were collected from Huzhou Central Hospital, China, from January 2006 to 2016, and 783 cases were excluded. This retrospective study illustrates the correlation between MMR status and prognosis for 1,757 CRC patients as well as the correlation between MSI and prognosis for CRC patients. Two groups were classified as MSI-H and MSI-L&MSS. If the expression of one or more mismatch repair (MMR) proteins was negative, it was considered as microsatellite instability high expression (MSI-H), whereas positive expression was considered as microsatellite instability low expression and microsatellite stability (MSI-L&MSS), as assessed by correlation analyses. Overall and disease-free survival were analyzed using the Kaplan-Meier method. Univariable and multivariable analyses were conducted using Cox regression. Results Preoperative serum S-CEA, positive lymph, tumor size, pathologic tumor (Pt) status, node (N) stage, differentiation, chemotherapy, and the 8th Edition of the American Joint Committee on Cancer (AJCC-8) were significantly correlated with MSI (P=0.028, 0.037, 0.019, 0.007, 0.002, <0.001, <0.001, and <0.001, respectively), whereas tumor location was not associated with MSI. Univariable and multivariable analyses showed that MSI was an independent factor for CRC. The 5-year overall survival (OS) and 5-year disease-free survival (DFS, P<0.001) rates differed significantly between the two groups in stages II, III, and IV, whereas stage I did not show a significant difference (P>0.05). Conclusion MSI-H was associated with a good prognosis for stages II to IV, whereas stage I did not show any significant correlation. Moreover, MSI expression was an independent prognostic factor.
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Affiliation(s)
- Guojun Tong
- Colorectal Surgery, Huzhou Central Hospital, The Affiliated Huzhou Central Hospital of Huzhou University, Zhejiang, China
- Central Laboratory, Huzhou Central Hospital, The Affiliated Huzhou Central Hopsital of Huzhou University, Zhejiang, China
| | - Guiyang Zhang
- Colorectal Surgery, Huzhou Central Hospital, The Affiliated Huzhou Central Hospital of Huzhou University, Zhejiang, China
| | - Yan Hu
- Department of English, Huzhou Vocational and Technical College, Zhejiang, China
| | - Xuting Xu
- Central Laboratory, Huzhou Central Hospital, The Affiliated Huzhou Central Hopsital of Huzhou University, Zhejiang, China
| | - Yanyan Wang
- Pathology Department, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Zhejiang, China
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25
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Wangmo D, Gates TJ, Zhao X, Sun R, Subramanian S. Centrosomal Protein 55 (CEP55) Drives Immune Exclusion and Resistance to Immune Checkpoint Inhibitors in Colorectal Cancer. Vaccines (Basel) 2024; 12:63. [PMID: 38250876 PMCID: PMC10820828 DOI: 10.3390/vaccines12010063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
Colorectal cancer (CRC) currently ranks as the third most common cancer in the United States, and its incidence is on the rise, especially among younger individuals. Despite the remarkable success of immune checkpoint inhibitors (ICIs) in various cancers, most CRC patients fail to respond due to intrinsic resistance mechanisms. While microsatellite instability-high phenotypes serve as a reliable positive predictive biomarker for ICI treatment, the majority of CRC patients with microsatellite-stable (MSS) tumors remain ineligible for this therapeutic approach. In this study, we investigated the role of centrosomal protein 55 (CEP55) in shaping the tumor immune microenvironment in CRC. CEP55 is overexpressed in multiple cancer types and was shown to promote tumorigenesis by upregulating the PI3K/AKT pathway. Our data revealed that elevated CEP55 expression in CRC was associated with reduced T cell infiltration, contributing to immune exclusion. As CRC tumors progressed, CEP55 expression increased alongside sequential mutations in crucial driver genes (APC, KRAS, TP53, and SMAD4), indicating its involvement in tumor progression. CEP55 knockout significantly impaired tumor growth in vitro and in vivo, suggesting that CEP55 plays a crucial role in tumorigenesis. Furthermore, the CEP55 knockout increased CD8+ T cell infiltration and granzyme B production, indicating improved anti-tumor immunity. Additionally, we observed reduced regulatory T cell infiltration in CEP55 knockout tumors, suggesting diminished immune suppression. Most significantly, CEP55 knockout tumors demonstrated enhanced responsiveness to immune checkpoint inhibition in a clinically relevant orthotopic CRC model. Treatment with anti-PD1 significantly reduced tumor growth in CEP55 knockout tumors compared to control tumors, suggesting that inhibiting CEP55 could improve the efficacy of ICIs. Collectively, our study underscores the crucial role of CEP55 in driving immune exclusion and resistance to ICIs in CRC. Targeting CEP55 emerges as a promising therapeutic strategy to sensitize CRC to immune checkpoint inhibition, thereby improving survival outcomes for CRC patients.
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Affiliation(s)
- Dechen Wangmo
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (D.W.); (T.J.G.); (X.Z.)
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Travis J. Gates
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (D.W.); (T.J.G.); (X.Z.)
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Xianda Zhao
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (D.W.); (T.J.G.); (X.Z.)
| | - Ruping Sun
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA;
- Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Subbaya Subramanian
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (D.W.); (T.J.G.); (X.Z.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA;
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
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26
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Naumov SS, Krakhmal NV, Tashireva LA, Vtorushin SV. [Expression of immune checkpoints PD-L1, CTLA4, LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status]. Arkh Patol 2024; 86:6-13. [PMID: 38591901 DOI: 10.17116/patol2024860216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2024]
Abstract
OBJECTIVE Study of the features of expression of immune checkpoint proteins PD-L1, CTLA4 and LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status. MATERIAL AND METHODS The study group consisted of 32 patients with a morphologically confirmed diagnosis of colon cancer; all of them underwent surgical treatment in the form of hemicolonectomy or resection. The work assessed samples of tumor tissue obtained as a result of surgery, the study was carried out in 3 stages: morphological examination of histological slides of colon tumors at the light-optical level, immunohistochemistry examination of tumor samples to determine the dMMR/pMMR status of carcinoma using a panel of antibodies to proteins of the unpaired nucleotide repair system MLH1, MSH2, MSH6 and PMS2, multiplex analysis of PD-L1, CTLA4, LAG3, CD3+, CD8+, CD163+ markers using the Vectra 3.0.3 tissue scanning system (Perkin Elmer, USA). RESULTS Significant differences in the expression of PD-L1, CTLA4, LAG3 in the area of the invasive tumor margin were revealed between the dMMR and pMMR groups of colon adenocarcinomas in patients comparable in clinical and morphological characteristics and treatment. In the group of tumors with dMMR status, an increase in the expression of all studied markers was noted. The number of CD3+ TILs was also significantly higher in the invasive margin of tumors with dMMR status. Similarly, in this group of colon carcinomas, a large number of CD163+ macrophages were noted both in the center and in the invasive margin zone. No statistically significant differences were found in the expression of immune checkpoints and the composition of TILs in the central zone of tumors with different MMR status. CONCLUSION A study using multiplex immunohistochemical analysis showed that MMR-deficient colon adenocarcinomas are characterized by more pronounced immune infiltration and increased expression of immune checkpoints in microenvironmental cells, mainly in the area of invasive tumor growth. The data obtained may be important for understanding the mechanisms of immune-mediated control of tumor growth and the choice of immunotherapy tactics depending on MMR status.
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Affiliation(s)
- S S Naumov
- Siberian State Medical University, Tomsk, Russia
| | - N V Krakhmal
- Siberian State Medical University, Tomsk, Russia
- Cancer Research Institute - Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
| | - L A Tashireva
- Cancer Research Institute - Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
| | - S V Vtorushin
- Siberian State Medical University, Tomsk, Russia
- Cancer Research Institute - Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
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27
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Laureano RS, Vanmeerbeek I, Sprooten J, Govaerts J, Naulaerts S, Garg AD. The cell stress and immunity cycle in cancer: Toward next generation of cancer immunotherapy. Immunol Rev 2024; 321:71-93. [PMID: 37937803 DOI: 10.1111/imr.13287] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 10/05/2023] [Accepted: 10/20/2023] [Indexed: 11/09/2023]
Abstract
The cellular stress and immunity cycle is a cornerstone of organismal homeostasis. Stress activates intracellular and intercellular communications within a tissue or organ to initiate adaptive responses aiming to resolve the origin of this stress. If such local measures are unable to ameliorate this stress, then intercellular communications expand toward immune activation with the aim of recruiting immune cells to effectively resolve the situation while executing tissue repair to ameliorate any damage and facilitate homeostasis. This cellular stress-immunity cycle is severely dysregulated in diseased contexts like cancer. On one hand, cancer cells dysregulate the normal cellular stress responses to reorient them toward upholding growth at all costs, even at the expense of organismal integrity and homeostasis. On the other hand, the tumors severely dysregulate or inhibit various components of organismal immunity, for example, by facilitating immunosuppressive tumor landscape, lowering antigenicity, and increasing T-cell dysfunction. In this review we aim to comprehensively discuss the basis behind tumoral dysregulation of cellular stress-immunity cycle. We also offer insights into current understanding of the regulators and deregulators of this cycle and how they can be targeted for conceptualizing successful cancer immunotherapy regimen.
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Affiliation(s)
- Raquel S Laureano
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Isaure Vanmeerbeek
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Jenny Sprooten
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Jannes Govaerts
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Stefan Naulaerts
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Abhishek D Garg
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
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Xu H, Jia Z, Liu F, Li J, Huang Y, Jiang Y, Pu P, Shang T, Tang P, Zhou Y, Yang Y, Su J, Liu J. Biomarkers and experimental models for cancer immunology investigation. MedComm (Beijing) 2023; 4:e437. [PMID: 38045830 PMCID: PMC10693314 DOI: 10.1002/mco2.437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 11/01/2023] [Accepted: 11/10/2023] [Indexed: 12/05/2023] Open
Abstract
The rapid advancement of tumor immunotherapies poses challenges for the tools used in cancer immunology research, highlighting the need for highly effective biomarkers and reproducible experimental models. Current immunotherapy biomarkers encompass surface protein markers such as PD-L1, genetic features such as microsatellite instability, tumor-infiltrating lymphocytes, and biomarkers in liquid biopsy such as circulating tumor DNAs. Experimental models, ranging from 3D in vitro cultures (spheroids, submerged models, air-liquid interface models, organ-on-a-chips) to advanced 3D bioprinting techniques, have emerged as valuable platforms for cancer immunology investigations and immunotherapy biomarker research. By preserving native immune components or coculturing with exogenous immune cells, these models replicate the tumor microenvironment in vitro. Animal models like syngeneic models, genetically engineered models, and patient-derived xenografts provide opportunities to study in vivo tumor-immune interactions. Humanized animal models further enable the simulation of the human-specific tumor microenvironment. Here, we provide a comprehensive overview of the advantages, limitations, and prospects of different biomarkers and experimental models, specifically focusing on the role of biomarkers in predicting immunotherapy outcomes and the ability of experimental models to replicate the tumor microenvironment. By integrating cutting-edge biomarkers and experimental models, this review serves as a valuable resource for accessing the forefront of cancer immunology investigation.
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Affiliation(s)
- Hengyi Xu
- State Key Laboratory of Molecular OncologyNational Cancer Center /National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ziqi Jia
- Department of Breast Surgical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Fengshuo Liu
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jiayi Li
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of Breast Surgical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yansong Huang
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of Breast Surgical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yiwen Jiang
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Pengming Pu
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Tongxuan Shang
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Pengrui Tang
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yongxin Zhou
- Eight‐year MD ProgramSchool of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yufan Yang
- School of MedicineTsinghua UniversityBeijingChina
| | - Jianzhong Su
- Oujiang LaboratoryZhejiang Lab for Regenerative Medicine, Vision, and Brain HealthWenzhouZhejiangChina
| | - Jiaqi Liu
- State Key Laboratory of Molecular OncologyNational Cancer Center /National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of Breast Surgical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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29
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Pecharromán I, Solé L, Álvarez‐Villanueva D, Lobo‐Jarne T, Alonso‐Marañón J, Bertran J, Guillén Y, Montoto Á, Martínez‐Iniesta M, García‐Hernández V, Giménez G, Salazar R, Santos C, Garrido M, Borràs E, Sabidó E, Bonfill‐Teixidor E, Iurlaro R, Seoane J, Villanueva A, Iglesias M, Bigas A, Espinosa L. IκB kinase-α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy. EMBO J 2023; 42:e114719. [PMID: 37737566 PMCID: PMC10620764 DOI: 10.15252/embj.2023114719] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/28/2023] [Accepted: 08/28/2023] [Indexed: 09/23/2023] Open
Abstract
Activation of the IκB kinase (IKK) complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-κB has remained elusive. Here, analysis of IKK-dependent substrates in CRC cells after UV treatment revealed that phosphorylation of BRD4 by IKK-α is required for its chromatin-binding at target genes upon DNA damage. Moreover, IKK-α induces the NF-κB-dependent transcription of the cytokine LIF, leading to STAT3 activation, association with BRD4 and recruitment to specific target genes. IKK-α abrogation results in defective BRD4 and STAT3 functions and consequently irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF-dependent IKK-α activity, BRD4, and the JAK/STAT pathway enhanced the therapeutic potential of 5-fluorouracil combined with irinotecan in CRC cells and is curative in a chemotherapy-resistant xenograft model. Finally, coordinated expression of LIF and IKK-α is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK-α, BRD4, and JAK/STAT signaling with clinical relevance.
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Affiliation(s)
- Irene Pecharromán
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - Laura Solé
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - Daniel Álvarez‐Villanueva
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
- Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)L'Hospitalet del LlobregatBarcelonaSpain
| | - Teresa Lobo‐Jarne
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - Josune Alonso‐Marañón
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - Joan Bertran
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
- Faculty of Science and TechnologyUniversity of Vic – Central University of CataloniaVicSpain
| | - Yolanda Guillén
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - Ángela Montoto
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - María Martínez‐Iniesta
- Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)L'Hospitalet del LlobregatBarcelonaSpain
| | - Violeta García‐Hernández
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - Gemma Giménez
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - Ramon Salazar
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)‐CIBERONCL'Hospitalet de LlobregatBarcelonaSpain
| | - Cristina Santos
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)‐CIBERONCL'Hospitalet de LlobregatBarcelonaSpain
| | - Marta Garrido
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
| | - Eva Borràs
- Proteomics Unit, Centre for Genomic Regulation (CRG)Barcelona Institute of Science and Technology (BIST)BarcelonaSpain
- Proteomics UnitUniversitat Pompeu FabraBarcelonaSpain
| | - Eduard Sabidó
- Proteomics Unit, Centre for Genomic Regulation (CRG)Barcelona Institute of Science and Technology (BIST)BarcelonaSpain
- Proteomics UnitUniversitat Pompeu FabraBarcelonaSpain
| | - Ester Bonfill‐Teixidor
- Vall d'Hebron Institute of Oncology (VHIO), CIBERONCVall d'Hebron University Hospital, Universitat Autònoma de BarcelonaBarcelonaSpain
| | - Raffaella Iurlaro
- Vall d'Hebron Institute of Oncology (VHIO), CIBERONCVall d'Hebron University Hospital, Universitat Autònoma de BarcelonaBarcelonaSpain
| | - Joan Seoane
- Vall d'Hebron Institute of Oncology (VHIO), CIBERONCVall d'Hebron University Hospital, Universitat Autònoma de BarcelonaBarcelonaSpain
- Institució Catalana de Recerca i Estudis Avançats (ICREA)BarcelonaSpain
| | - Alberto Villanueva
- Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)L'Hospitalet del LlobregatBarcelonaSpain
- Xenopat S.L., Parc Cientific de Barcelona (PCB)BarcelonaSpain
| | - Mar Iglesias
- Department of Pathology, Institut Mar d'Investigacions Mèdiques, CIBERONCUniversitat Autònoma de BarcelonaBarcelonaSpain
| | - Anna Bigas
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
- Josep Carreras Leukemia Research InstituteBadalonaSpain
| | - Lluís Espinosa
- Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONCHospital del MarBarcelonaSpain
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Cheng Y, Chang F, Gong Y, Lu P. A Study on the Clinical Significance of Blood Exosomal PD-L1 in Non-Small Cell Lung Cancer Patients and its Correlation with PD-L1 in Tumor Tissues. Horm Metab Res 2023; 55:788-793. [PMID: 37459865 DOI: 10.1055/a-2110-7497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/01/2023]
Abstract
Exosomal programmed cell-death ligand 1 (ePD-L1) can influence immune inhibition and dysfunction. We were dedicated to unearthing the relation between ePD-L1 in blood and pathological characteristics as well as PD-L1 in tumor tissues. We recruited 65 non-small cell lung cancer (NSCLC) patients for exosome extraction and detected the blood ePD-L1 expression in these patients by enzyme-linked immunosorbent assay (ELISA) method. Besides, the correlation between blood ePD-L1 and patients' pathological characteristics was also analyzed. The expression of PD-L1 in tumor tissues was tested by immunohistochemistry (IHC) and its correlation with blood ePD-L1 expression level was analyzed by Spearman correlation coefficient. No significant correlation was observed in PD-L1 expression levels between blood-derived exosome and tumor tissue. Altogether, high blood ePD-L1 expression was relevant to NSCLC progression, while no such relevance to PD-L1 expression in tumor tissue.
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Affiliation(s)
- Yonghong Cheng
- Department of Oncology, Shanxi Jishan County People's Hospital, Yuncheng, China
| | - Feiyun Chang
- Department of Thoracic Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Yanmei Gong
- Department of Oncology, Shanxi Yuncheng Center Hospital, Yuncheng, China
| | - Ping Lu
- Department of Radiotherapy Head and Neck Comprehensive Ward, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
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Chen L, Zhao R, Shen J, Liu N, Zheng Z, Miao Y, Zhu J, Zhang L, Wang Y, Fang H, Zhou J, Li M, Yang Y, Liu Z, Chen Q. Antibacterial Fusobacterium nucleatum-Mimicking Nanomedicine to Selectively Eliminate Tumor-Colonized Bacteria and Enhance Immunotherapy Against Colorectal Cancer. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2306281. [PMID: 37722134 DOI: 10.1002/adma.202306281] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/28/2023] [Indexed: 09/20/2023]
Abstract
Clinical evidence indicates that tumor-colonizing bacteria can be closely related to the tumor development and therapeutic responses. Selectively eliminating bacteria within tumors may be an attractive approach to enhance cancer treatment without additional side effects. Herein, it is found that, owing to the high affinity between the membrane protein Fap-2 on Fusobacterium nucleatum and d-galactose-β (1-3)-N-acetyl-d-galactosamine (Gal-GalNAc) overexpressed on colorectal tumor cells, F. nucleatum can colonize in colorectal tumors, as evidenced by both clinical samples and animal tumor models. Notably, F. nucleatum colonized in colorectal tumors can lead to an immunosuppressive tumor microenvironment, greatly reducing their responses to immune checkpoint blockade (ICB) therapy. Inspired by this finding, an F. nucleatum-mimetic nanomedicine is designed by fusing F. nucleatum cytoplasmic membrane (FM) with Colistin-loaded liposomes to achieve selective killing of tumor-colonizing F. nucleatum without affecting gut microbes. As a result, the therapeutic responses of F. nucleatum-colonized tumors to ICB therapies can be successfully restored, as demonstrated in an F. nucleatum-infected subcutaneous CT-26 tumor model, chemically induced spontaneous colorectal cancer models, and MC-38 tumor model. In summary, this work presents an F. nucleatum-mimicking nanomedicine that can selectively eliminate tumor-colonized bacteria, which is promising for enhancing the responses of cancer immunotherapy against F. nucleatum-colonized colorectal cancer.
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Affiliation(s)
- Linfu Chen
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Rui Zhao
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Jingjing Shen
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Nanhui Liu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Zixuan Zheng
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China
| | - Yu Miao
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Jiafei Zhu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Lin Zhang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, P.R. China
| | - Yingyao Wang
- Department of Gynecology, Kunshan Maternity and Children's Health Care Hospital, Suzhou, Jiangsu, 215300, P.R. China
| | - Huapan Fang
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Jun Zhou
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Maoyi Li
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Yang Yang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China
| | - Zhuang Liu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
| | - Qian Chen
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P.R. China
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Khamisi S, Anders Karlsson F, Ljunggren Ö, Thulin M, Larsson A. Increased plasma levels of soluble programmed death ligand 1 (sPD-L1) and fibroblast growth factor 23 (FGF-23) in patients with Graves' ophthalmopathy in comparison to hyperthyroid patients without Graves' ophthalmopathy. Cytokine 2023; 169:156269. [PMID: 37307688 DOI: 10.1016/j.cyto.2023.156269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 05/19/2023] [Accepted: 06/06/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND Management of Graves' ophthalmopathy (GO) is still a challenge in Graves' disease (GD). Moreover, 40% of GD patients show radiological muscle enlargement without clinically apparent GO. Delayed treatment of GO may lead to deterioration in prognosis. METHODS Thirty GD patients with overt hyperthyroidism were included in this study, 17 of whom either had GO at diagnosis or developed GO during the study period. Samples were collected at the beginning of the study, at 6 months, and at 24 months. Plasma samples were analyzed for 92 cytokines using the Olink Target 96 inflammation panel. RESULTS After adjustment for multiplicity testing using the false discovery rate approach, soluble programmed death ligand 1 (sPD-L1) and fibroblast growth factor 23 (FGF-23) were significantly elevated in GO patients. CONCLUSION Using a broad cytokine panel we show that patients with Graves' ophthalmopathy have elevated PD-L1 and FGF-23 levels. The findings support previous suggestions that PD-L1 may serve as a treatment target.
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Affiliation(s)
- Selwan Khamisi
- Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
| | - F Anders Karlsson
- Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
| | - Östen Ljunggren
- Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
| | - Mans Thulin
- Department of Statistics, Uppsala University, Uppsala, Sweden
| | - Anders Larsson
- Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
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Du HX, Hong CX, Yu T. Carrilizumab for treatment of advanced colorectal cancer: Short-term efficacy and impact on immune function and PD-1/PD-L1 signaling pathway. Shijie Huaren Xiaohua Zazhi 2023; 31:647-654. [DOI: 10.11569/wcjd.v31.i15.647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 07/23/2023] [Accepted: 08/04/2023] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND Colorectal cancer is one of the most prevalent malignant tumours in China, and chemotherapy is the main treatment modality for patients with advanced colorectal cancer, which results in toxic side effects and reduces patients' quality of life. Since the occurrence of toxic side effects is related to patients' immunity and other factors, it is important to study whether the combined injection of carrilizumab with chemotherapy can positively affect patients' conditions by influencing the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) signalling pathway.
AIM To investigate the possible mechanism of carrilizumab for injection to improve immune function in advanced colorectal cancer, and to analyze its regulatory effect on the PD-1/ PD-L1 signaling pathway.
METHODS A prospective randomised controlled study (RCT) was performed to include 127 patients with advanced colorectal cancer admitted to our hospital from January 2019 to October 2021, and they were divided into a control group (n = 63) and a study group (n = 64) using the computerised random number method. The control group was given oxaliplatin + capecitabine, and the study group was given oxaliplatin + capecitabine + carrilizumab for injection. The therapeutic effect, toxicity and side effects, survival status, PD-1/PD-L1 signaling pathway, tumor markers [carbohydrate antigen 125 (CA125), carbohydrate antigen 242 (CA242), thymidine kinase 1 (TK1), and carcinoembryonic antigen (CEA)], and nutritional status indicators [albumin (ALB), hemoglobin (HGB), prealbumin (PA), transferrin (TF), and patient-generated subjective global assessment (PG-SGA)] before and after treatment were compared between the two groups.
RESULTS After four cycles of treatment, the disease control rate of the study group was higher than that of the control group (P < 0.05); the mRNA and protein levels of PD-1 and PD-L1 in the study group were lower than those in the control group (P < 0.05); serum ALB, PA, and TF levels and PG-SGA scores in the study group were higher than those in the control group (P < 0.05); and serum CA125, CA242, TK1, and CEA in the study group were lower than those in the control group (P < 0.05). There was no significant difference in the incidence of toxic and side effects or survival rate between the two groups (P > 0.05).
CONCLUSION Camrelizumab for injection combined with oxaliplatin and capecitabine in the treatment of advanced colorectal cancer can improve the disease control rate, may reduce the impact of chemotherapy drugs on the nutritional status of the body by inhibiting the activation of PD-1/PD-L1 signal pathway, thus improving the immune function of the body, and has good safety.
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Affiliation(s)
- Hai-Xu Du
- Department of Pharmacy, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Chun-Xia Hong
- Department of Pharmacy, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Tong Yu
- Department of Pharmacy, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
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Li C, Yu F, Xu W. Early low blood MALT1 expression levels forecast better efficacy of PD‑1 inhibitor‑based treatment in patients with metastatic colorectal cancer. Oncol Lett 2023; 26:329. [PMID: 37415633 PMCID: PMC10320427 DOI: 10.3892/ol.2023.13915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 01/30/2023] [Indexed: 07/08/2023] Open
Abstract
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) modulates colorectal cancer (CRC) malignant behaviors and tumor immune escape. The present study aimed to explore the association of MALT1 with treatment response and survival time among patients with metastatic CRC (mCRC) after programmed cell death protein-1 (PD-1) inhibitor-based treatment. MALT1 from the blood samples of 75 patients with unresectable mCRC receiving PD-1 inhibitor-based treatment at baseline and after 2-cycle treatment, as well as 20 healthy controls (HCs), was detected by reverse transcription-quantitative PCR. In the patients with mCRC, the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were calculated. MALT1 expression was elevated in patients with mCRC compared with that in HCs (P<0.001). In patients with mCRC, MALT1 expression was positively correlated with multiple (vs. single) metastasis (P=0.032) and peritoneum metastasis (P=0.029). MALT1 levels before treatment were decreased in ORR patients vs. non-ORR patients (P=0.043) and in DCR patients vs. non-DCR patients (P=0.007). Additionally, MALT1 expression was reduced after treatment compared with that before treatment (P<0.001). Meanwhile, MALT1 expression after treatment was notably decreased in ORR patients vs. non-ORR patients (P<0.001) and in DCR patients vs. non-DCR patients (P<0.001). Furthermore, a low MALT1 level before treatment was associated with longer PFS (P=0.030) and OS (P=0.025) times. Decreased MALT1 expression after treatment and a decline in MALT1 expression of >30% after treatment (ratio to MALT1 before treatment) (both P≤0.001) presented more significant associations with prolonged PFS and OS times. In conclusion, early low levels of blood MALT1 during therapy may predict an improved response to PD-1 inhibitor-based treatment and survival time in patients with mCRC.
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Affiliation(s)
- Chuanming Li
- Department of Anorectal Surgery, Wuhan No. 8 Hospital (Wuhan Anorectal Hospital), Wuhan, Hubei 430000, P.R. China
| | - Fan Yu
- Department of Anorectal Surgery, Wuhan No. 8 Hospital (Wuhan Anorectal Hospital), Wuhan, Hubei 430000, P.R. China
| | - Wanli Xu
- Department of Gastroenterology, Wuhan No. 8 Hospital (Wuhan Anorectal Hospital), Wuhan, Hubei 430000, P.R. China
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Ozer M, Vegivinti CTR, Syed M, Ferrell ME, Gonzalez Gomez C, Cheng S, Holder-Murray J, Bruno T, Saeed A, Sahin IH. Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm. Cancers (Basel) 2023; 15:3833. [PMID: 37568648 PMCID: PMC10417711 DOI: 10.3390/cancers15153833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/19/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, particularly colorectal cancer. Cancers with the MMR-D/MSI-H genotype often carry a higher tumor mutation burden with frameshift alterations, leading to increased mutation-associated neoantigen (MANA) generation. The dramatic response seen with immune checkpoint inhibitors (ICIs), which are orchestrated by MANA-primed effector T cells, resulted in the rapid development of these novel therapeutics within the landscape of MSI-H gastrointestinal cancers. Recently, several clinical trials have utilized ICIs as potential neoadjuvant therapies for MSI-H gastrointestinal cancers and demonstrated deep clinical and pathological responses, creating opportunities for organ preservation. However, there are potential challenges to the neoadjuvant use of ICIs for certain disease types due to the clinical risk of overtreatment for a disease that can be cured through a surgery-only approach. In this review article, we discuss neoadjuvant management approaches with ICI therapy for patients with MSI-H gastrointestinal cancers, including those with oligometastatic disease. We also elaborate on potential challenges and opportunities for the neoadjuvant utilization of ICIs and provide further insight into the changing treatment paradigm of MMR-D/MSI-H gastrointestinal cancers.
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Affiliation(s)
- Muhammet Ozer
- Department of Gastrointestinal Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
| | | | - Masood Syed
- Department of Medicine, University of Pittsburg School of Medicine, Pittsburgh, PA 15213, USA
| | - Morgan E. Ferrell
- Department of Medicine, University of Pittsburg School of Medicine, Pittsburgh, PA 15213, USA
| | - Cyndi Gonzalez Gomez
- Department of Medicine, University of Pittsburg School of Medicine, Pittsburgh, PA 15213, USA
| | - Svea Cheng
- Department of Medicine, University of Pittsburg School of Medicine, Pittsburgh, PA 15213, USA
| | - Jennifer Holder-Murray
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Tullia Bruno
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Anwaar Saeed
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Ibrahim Halil Sahin
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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Wang L, Yang Z, Guo F, Chen Y, Wei J, Dai X, Zhang X. Research progress of biomarkers in the prediction of anti-PD-1/PD-L1 immunotherapeutic efficiency in lung cancer. Front Immunol 2023; 14:1227797. [PMID: 37465684 PMCID: PMC10351040 DOI: 10.3389/fimmu.2023.1227797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/13/2023] [Indexed: 07/20/2023] Open
Abstract
Currently, anti-PD-1/PD-L1 immunotherapy using immune checkpoint inhibitors is widely used in the treatment of multiple cancer types including lung cancer, which is a leading cause of cancer death in the world. However, only a limited proportion of lung cancer patients will benefit from anti-PD-1/PD-L1 therapy. Therefore, it is of importance to predict the response to immunotherapy for the precision treatment of patients. Although the expression of PD-L1 and tumor mutation burden (TMB) are commonly used to predict the clinical response of anti-PD-1/PD-L1 therapy, other factors such as tumor-specific genes, dMMR/MSI, and gut microbiome are also promising predictors for immunotherapy in lung cancer. Furthermore, invasive peripheral blood biomarkers including blood DNA-related biomarkers (e.g., ctDNA and bTMB), blood cell-related biomarkers (e.g., immune cells and TCR), and other blood-related biomarkers (e.g., soluble PD-L1 and cytokines) were utilized to predict the immunotherapeutic response. In this review, the current achievements of anti-PD-1/PD-L1 therapy and the potential biomarkers for the prediction of anti-PD-1/PD-L1 immunotherapy in lung cancer treatment were summarized and discussed.
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Affiliation(s)
- Luyao Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Zongxing Yang
- Department of Clinical Laboratory, First Hospital of Jilin University, Changchun, China
| | - Fucheng Guo
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Yurong Chen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Jiarui Wei
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Xiangpeng Dai
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Xiaoling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
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Li Y, Xue C, Gao Z, Li K, Xu H, Zhu Z. Efficacy of neoadjuvant immunotherapy in advanced colorectal cancer: a meta-analysis of cross-sectional studies. J Cancer Res Clin Oncol 2023; 149:4839-4846. [PMID: 36260157 DOI: 10.1007/s00432-022-04402-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/05/2022] [Indexed: 10/24/2022]
Abstract
BACKGROUND Although neoadjuvant immunotherapy is being widely studied, there is no consensus on its efficacy in microsatellite-stable (MSS) or mismatch repair proficient (pMMR) colorectal cancer (CRC). This meta-analysis aimed to evaluate studies on neoadjuvant immunotherapy for advanced CRC to assess its efficacy and provide new clinical guidelines. METHODS We searched literature databases to identify studies that assessed the efficacy of neoadjuvant immunotherapy in advanced CRC. The outcomes evaluated were pathological complete response (pCR), major pathological response (MPR), R0 resection, and anal preservation rates. Heterogeneity among the included studies was assessed by sensitivity analysis, and publication bias was evaluated using Begg and Egger tests. RESULTS Eleven articles were included in the analysis. The pCR, MPR, R0 resection, and anal preservation rates reported in these studies were 39 and 49, 97, and 76%, respectively. The MSI-H and MSS groups had pooled pCR rates of 70 and 24%, respectively. The pCR rates for the induction, consolidation, and concurrent immuno-chemoradiotherapy (CRT) subgroups were 43, 33, and 27%, respectively, and those for the single and double immunotherapy subgroups were 34 and 40%, respectively. CONCLUSION Neoadjuvant immunotherapy combined with CRT is effective in treating MSI-H/dMMR advanced CRC. It could also be a new first-line therapeutic option for MSS/pMMR advanced CRC.
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Affiliation(s)
- Yuegang Li
- Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People's Republic of China
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, 065001, China
| | - Chi Xue
- Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Ziming Gao
- Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Kai Li
- Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Huimian Xu
- Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Zhi Zhu
- Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People's Republic of China.
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Wang H, Luo K, Zhan Y, Peng S, Fan S, Wang W. Role of β-catenin in PD-L1 expression of nasopharyngeal carcinoma. Heliyon 2023; 9:e18130. [PMID: 37496925 PMCID: PMC10366426 DOI: 10.1016/j.heliyon.2023.e18130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 07/05/2023] [Accepted: 07/07/2023] [Indexed: 07/28/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a particular type of tumor connected to Epstein-Barr virus infection, genetic, and environmental factors. It is typically discovered late, with few therapeutic options and poor clinical outcomes. Cellular immune responses can be attenuated when programmed death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) are combined. Although PD-1 inhibitors have a different anti-tumor response rate than chemotherapy alone, they can nevertheless considerably outperform chemotherapy in patients with metastatic or recurrent NPC. The nuclear β-catenin can bind to the CD274 promoter region, promoting transcription and upregulating the expression of tumor-specific PD-L1. Separation of β-catenin from E-cadherin and translocation it into nucleus were both aided by β-catenin phosphorylates at the Tyr654 site. Its function in NPC and the expression of PD-L1 have not yet been investigated. This study investigated the predictive significance of PD-L1 and p-β-cateninTyr654 expressions in NPC. Our findings indicated that patients with distant metastases or poor prognoses exhibited higher levels of PD-L1 and p-β-cateninTyr654 expressions. According to Cox multivariate prognostic analysis, PD-L1 was also an effective indicator for predicting the survival status of patients with NPC. We subsequently demonstrated that PD-L1 transcription and protein production could be downregulated by targeting inhibition of the level of β-catenin in NPC cells. This is for developing the β-catenin or TCF4 inhibitor as a potential new option for immune checkpoint immunosuppression in NPC.
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Affiliation(s)
- Haihua Wang
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Kaiju Luo
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Yuting Zhan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - shuping Peng
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Weiyuan Wang
- Department of Pathology, The Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
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Wu R, Tong S, Yin J, Zhu Z, Mao Z, Xu L. Oncolytic vaccinia virus acts synergistically with anti-PD-L1 antibody to enhance the killing of colon cancer cells by CD8 + T cells. Pathol Res Pract 2023; 247:154535. [PMID: 37257241 DOI: 10.1016/j.prp.2023.154535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 04/11/2023] [Accepted: 05/11/2023] [Indexed: 06/02/2023]
Abstract
Both oncolytic vaccinia virus (OVV) and anti-PD-L1 antibody hold promise in cancer immunotherapy. Herein, we aimed to explore the possible synergistic effects of OVV and anti-PD-L1 on the growth and metastasis of colon cancer (CC) in mouse models. Microarray profiling of CC-related genes was first conducted. Expression of PD-L1 in CC tissues was predicted by TCGA and verified by flow cytometry and RT-qPCR. Then, mouse CC cell lines stably carrying luciferase MC38-luc and CT26-luc were infected with recombinant double-deleted vaccinia virus (vvDD) to evaluate the effect of vvDD on cell viability. The data indicated that PD-L1 was highly expressed in CC tissues and cells following vvDD infection. MC38-luc cells were inoculated into mice to construct CC-bearing mouse models, which were treated with vvDD or combined with anti-PD-L1, with tumor growth, metastasis, survival, and the immune environment analyzed. It was found that OVV combined with anti-PD-L1 antibody led to lower tumor burden and growth and higher survival rates than individual treatment in CC-bearing mice. In addition, this combination exerted a remote effect on the untreated subcutaneous tumors in the lateral abdomen, thus suppressing the tumor metastasis. Furthermore, combined therapy of OVV with anti-PD-L1 antibody activated CD8+ T cells, reduced exhaustion of CD8+ T cells, and enhanced their immune response, strengthening the killing of CC cells and inhibiting tumor growth and metastasis. In conclusion, our findings provide mechanistic insights into the action and efficacy of OVV as an immunomodulatory agent combined with the anti-PD-L1 antibody for the treatment of CC.
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Affiliation(s)
- Runda Wu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, PR China
| | - Shan Tong
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, PR China
| | - Jun Yin
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, PR China
| | - Zheng Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, PR China
| | - Zhongqi Mao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, PR China.
| | - Lu Xu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, PR China.
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Ding JT, Yang KP, Zhou HN, Huang YF, Li H, Zong Z. Landscapes and mechanisms of CD8 + T cell exhaustion in gastrointestinal cancer. Front Immunol 2023; 14:1149622. [PMID: 37180158 PMCID: PMC10166832 DOI: 10.3389/fimmu.2023.1149622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 04/13/2023] [Indexed: 05/15/2023] Open
Abstract
CD8+ T cells, a cytotoxic T lymphocyte, are a key component of the tumor immune system, but they enter a hyporeactive T cell state in long-term chronic inflammation, and how to rescue this depleted state is a key direction of research. Current studies on CD8+ T cell exhaustion have found that the mechanisms responsible for their heterogeneity and differential kinetics may be closely related to transcription factors and epigenetic regulation, which may serve as biomarkers and potential immunotherapeutic targets to guide treatment. Although the importance of T cell exhaustion in tumor immunotherapy cannot be overstated, studies have pointed out that gastric cancer tissues have a better anti-tumor T cell composition compared to other cancer tissues, which may indicate that gastrointestinal cancers have more promising prospects for the development of precision-targeted immunotherapy. Therefore, the present study will focus on the mechanisms involved in the development of CD8+ T cell exhaustion, and then review the landscapes and mechanisms of T cell exhaustion in gastrointestinal cancer as well as clinical applications, which will provide a clear vision for the development of future immunotherapies.
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Affiliation(s)
- Jia-Tong Ding
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical Medicine School, Nanchang University, Nanchang, China
| | - Kang-Ping Yang
- The Second Clinical Medicine School, Nanchang University, Nanchang, China
| | - Hao-Nan Zhou
- Queen Mary School, Nanchang University, Nanchang, China
| | - Ying-Feng Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hui Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Kula A, Dawidowicz M, Mielcarska S, Kiczmer P, Skiba H, Krygier M, Chrabańska M, Piecuch J, Szrot M, Robotycka J, Ochman B, Strzałkowska B, Czuba Z, Świętochowska E, Waniczek D. Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer. Int J Mol Sci 2023; 24:ijms24065876. [PMID: 36982953 PMCID: PMC10057377 DOI: 10.3390/ijms24065876] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/12/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
The study aimed to investigate correlations between HHLA2 levels and parameters, including microsatellite instability (MSI) status, CD8+ cells, and histopathological features: budding, tumor-infiltrating lymphocytes (TILs), TNM scale, grading, cytokines, chemokines, and cell signaling moleculesin colorectal cancer (CRC). Furthermore, the immune infiltration landscape and HHLA2-related pathways in colorectal cancer using available online datasets were analyzed. The study included 167 patients diagnosed with CRC. Expression of HHLA2 was detected by immunohistochemistry method (IHC) and enzyme-linked immunosorbent assay (ELISA). The IHC was used to evaluate the MSI and CD8+ status. The budding and TILs were measured using a light microscope. The concentrations of cytokines, chemokines, and cell signaling molecules were measured to analyze the data by the Bio-Plex Pro Human cytokine screening panel, 48 cytokine assay, and principal component analysis (PCA). Geneset enrichment analysis (GSEA) was conducted to identify HHLA2-related pathways. The biological function of HHLA2 was predicted by Gene Ontology (GO). Analysis of the immune infiltration landscape of HHLA2 in colorectal cancer was made by the web-based tool Camoip. High HHLA2 expression was detected in CRC tumor tissues compared to the adjacent noncancerous tissues. The percentage of HHLA2-positive tumors was 97%. GSEA and GO showed that HHLA2 upregulation correlated with cancer-related pathways and several biological functions. Tumor-infiltrating lymphocytes score correlated positively with IHC HHLA2 expression level percentage. There was a negative correlation between HHLA2, anti-tumor cytokines and pro-tumor growth factors. This study provides a valuable insight into the role of HHLA2 in CRC. We reveal the role of HHLA2 expression as well as a stimulatory and inhibitory immune checkpoint in colorectal cancer. Further research may verify the therapeutic values of the HHLA2-KIR3DL3/TMIGD2 pathway in colorectal cancer.
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Affiliation(s)
- Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Paweł Kiczmer
- Department and Chair of Pathomorphology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 13-15 3 Maja, 41-800 Zabrze, Poland
| | - Hanna Skiba
- Department and Chair of Pathomorphology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 13-15 3 Maja, 41-800 Zabrze, Poland
| | - Małgorzata Krygier
- Department and Chair of Pathomorphology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 13-15 3 Maja, 41-800 Zabrze, Poland
| | - Magdalena Chrabańska
- Department and Chair of Pathomorphology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 13-15 3 Maja, 41-800 Zabrze, Poland
| | - Jerzy Piecuch
- Department of General and Bariatric Surgery and Emergency Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Monika Szrot
- Department of General and Bariatric Surgery and Emergency Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Julia Robotycka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Błażej Ochman
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Bogumiła Strzałkowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Zenon Czuba
- Department of Microbiology and Immunology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
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Kciuk M, Kołat D, Kałuzińska-Kołat Ż, Gawrysiak M, Drozda R, Celik I, Kontek R. PD-1/PD-L1 and DNA Damage Response in Cancer. Cells 2023; 12:530. [PMID: 36831197 PMCID: PMC9954559 DOI: 10.3390/cells12040530] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/29/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023] Open
Abstract
The application of immunotherapy for cancer treatment is rapidly becoming more widespread. Immunotherapeutic agents are frequently combined with various types of treatments to obtain a more durable antitumor clinical response in patients who have developed resistance to monotherapy. Chemotherapeutic drugs that induce DNA damage and trigger DNA damage response (DDR) frequently induce an increase in the expression of the programmed death ligand-1 (PD-L1) that can be employed by cancer cells to avoid immune surveillance. PD-L1 exposed on cancer cells can in turn be targeted to re-establish the immune-reactive tumor microenvironment, which ultimately increases the tumor's susceptibility to combined therapies. Here we review the recent advances in how the DDR regulates PD-L1 expression and point out the effect of etoposide, irinotecan, and platinum compounds on the anti-tumor immune response.
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Affiliation(s)
- Mateusz Kciuk
- Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
| | - Damian Kołat
- Department of Experimental Surgery, Faculty of Medicine, Medical University of Lodz, Narutowicza 60, 90-136 Lodz, Poland
| | - Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Faculty of Medicine, Medical University of Lodz, Narutowicza 60, 90-136 Lodz, Poland
| | - Mateusz Gawrysiak
- Department of Immunology and Allergy, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
| | - Rafał Drozda
- Department of Gastrointestinal Endoscopy, Wl. Bieganski Hospital, 91-347 Lodz, Poland
| | - Ismail Celik
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
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De S, Paul S, Manna A, Majumder C, Pal K, Casarcia N, Mondal A, Banerjee S, Nelson VK, Ghosh S, Hazra J, Bhattacharjee A, Mandal SC, Pal M, Bishayee A. Phenolic Phytochemicals for Prevention and Treatment of Colorectal Cancer: A Critical Evaluation of In Vivo Studies. Cancers (Basel) 2023; 15:993. [PMID: 36765950 PMCID: PMC9913554 DOI: 10.3390/cancers15030993] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as "colorectal cancer" AND "phenolic compounds", "colorectal cancer" AND "polyphenol", "colorectal cancer" AND "phenolic acids", "colorectal cancer" AND "flavonoids", "colorectal cancer" AND "stilbene", and "colorectal cancer" AND "lignan" from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC.
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Affiliation(s)
- Samhita De
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Sourav Paul
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | - Anirban Manna
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | | | - Koustav Pal
- Jawaharlal Institute Post Graduate Medical Education and Research, Puducherry 605 006, India
| | - Nicolette Casarcia
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Arijit Mondal
- Department of Pharmaceutical Chemistry, M.R. College of Pharmaceutical Sciences and Research, Balisha 743 234, India
| | - Sabyasachi Banerjee
- Department of Pharmaceutical Chemistry, Gupta College of Technological Sciences, Asansol 713 301, India
| | - Vinod Kumar Nelson
- Department of Pharmacology, Raghavendra Institute of Pharmaceutical Education and Research, Anantapur 515 721, India
| | - Suvranil Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Joyita Hazra
- Department of Biotechnology, Indian Institute of Technology, Chennai 600 036, India
| | - Ashish Bhattacharjee
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | | | - Mahadeb Pal
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
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Cao Y, Lu M, Sun Y, Gong J, Li J, Lu Z, Li J, Zhang X, Li Y, Peng Z, Zhou J, Wang X, Shen L. Surufatinib plus toripalimab in patients with advanced solid tumors: a single-arm, open-label, phase 1 trial. J Cancer Res Clin Oncol 2023; 149:779-789. [PMID: 35166929 PMCID: PMC9931771 DOI: 10.1007/s00432-021-03898-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 12/21/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE This phase 1 trial evaluated the safety, preliminary efficacy, and pharmacokinetics of surufatinib, a small molecular tyrosine kinase inhibitor, combined with toripalimab, a programmed cell death protein-1 antibody, in patients with advanced solid tumors. METHODS This is an open-label, dose-escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose-escalation stage, patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with toripalimab 240 mg, every 3 weeks (Q3W), to estimate maximum tolerated dose. Additional patients were enrolled in the dose expansion stage to further assess the efficacy, safety, and pharmacokinetics profile. Recommended phase 2 dose (RP2D) was determined based on the safety, tolerability, and preliminary efficacy from dose-escalation and expansion stages. RESULTS From Feb 14, 2019 to Dec 20, 2020, 33 patients were screened, of which 30 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity, a grade 3 hyperthyroidism. The most frequent treatment-related adverse events of grade ≥ 3 were hypertension (20.0%), transaminases increased (13.3%), and blood bilirubin increased (13.3%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Objective response rate was 24.1% (95% confidence interval 10.3‒43.5%) in this study. CONCLUSIONS Surufatinib plus toripalimab was well tolerated, with no unexpected safety signals, and showed preliminary anti-tumor activity in patients with advanced solid tumors. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT03879057; registration date: March 18, 2019.
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Affiliation(s)
- Yanshuo Cao
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Yu Sun
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jifang Gong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Jie Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Zhihao Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Yan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Jun Zhou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.
- Department of Early Drug Development Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
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Zhou L, Yang XQ, Zhao GY, Wang FJ, Liu X. Meta-analysis of neoadjuvant immunotherapy for non-metastatic colorectal cancer. Front Immunol 2023; 14:1044353. [PMID: 36776899 PMCID: PMC9911889 DOI: 10.3389/fimmu.2023.1044353] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 01/16/2023] [Indexed: 01/28/2023] Open
Abstract
Background Immunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of non-metastatic colorectal cancer remains unclear. We tried to explore clinical effect of neoadjuvant immunotherapy in the treatment of non-metastatic colorectal cancer. Methods We searched the databases (PubMed, Wanfang Embase, Cochrane Library and China National Knowledge Infrastructure databases) to obtain suitable articles up to September 2022. The primary outcomes of pathological complete response (pCRs), major pathological response (MPR), objective response rate (ORR), R0-resection and anus preserving rate were collected and evaluated. Secordary outcomes (pCRs and MPR) of subgroup analysis between deficient mismatch repair/microsatellite instability-high group (dMMR/MSI-H) and proficient mismatch repair/microsatellite stable group (pMMR/MSS) and outcomes for rectal cancer were analyzed for the final results. Results We included ten articles and 410 cases of non-metastatic colorectal cancer with neoadjuvant immunotherapy. There were 113 (27.5%) cases with the dMMR/MSI-H status and 167 (40.7%) cases with the pMMR/MSS status. pCRs was found in 167/373 (44.6%) patients (ES: 0.49, 95% CI: 0.36 to 0.62, P<0.01, chi2 = 65.3, P<0.01, I 2 = 86.2%) and MPR was found in 194/304 (63.8%) patients (ES: 0.66, 95% CI: 0.54 to 0.78, P<0.01, chi2 = 42.55, P<0.01, I 2 = 81.2%) with the random-effects model and huge heterogeneity. In the subgroup analysis, pCRs was higher in the dMMR/MSI-H group than the pMMR/MSS group in the fixed-effects model with minimal heterogeneity (OR: 3.55, 95% CI: 1.74 to 7.27, P<0.01, chi2 = 1.86, P=0.6, I 2 = 0%). pCRs was found in 58/172 (33.9%) rectal cancer patients (ES: 0.33, 95% CI: 0.26 to 0.40, P<0.01, chi2 = 3.04, P=0.55, I 2 = 0%) with the fixed-effects model and little heterogeneity. Conclusion Neoadjuvant immunotherapy could increase pCRs and MPR rate for non-metastatic colorectal cancer. Neoadjuvant immunotherapy could achieve better pCRs rate in dMMR/MSI-H group than in the pMMR/MSS group. Neoadjuvant immunotherapy could be another treatment option for non-metastatic colorectal cancer. Systematic review registration https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42022350523.
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Affiliation(s)
- Long Zhou
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiao-Quan Yang
- Department of General Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Guang-yue Zhao
- Department of Colorectal Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Feng-jian Wang
- Department of Colorectal Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xin Liu
- Department of Colorectal Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China,*Correspondence: Xin Liu,
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Luo J, Chen C, Liu Z, Wang X. The mutation in splicing factor genes correlates with unfavorable prognosis, genomic instability, anti-tumor immunosuppression and increased immunotherapy response in pan-cancer. Front Cell Dev Biol 2023; 10:1045130. [PMID: 36684432 PMCID: PMC9852835 DOI: 10.3389/fcell.2022.1045130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/21/2022] [Indexed: 01/09/2023] Open
Abstract
Splicing abnormality resulting from somatic mutations in key splicing factor genes (SFG) has been detected in various cancers. Hence, an in-depth study of splicing factor genes mutations' impact on pan-cancer is meaningful. This study investigated associations of splicing factor genes mutations with clinical features, tumor progression phenotypes, genomic integrity, anti-tumor immune responses, and immunotherapy response in 12 common cancer types from the TCGA database. Compared to SFG-wildtype cancers, SFG-mutated cancers displayed worse survival prognosis, higher tumor mutation burden and aneuploidy levels, higher expression of immunosuppressive signatures, and higher levels of tumor stemness, proliferation potential, and intratumor heterogeneity (ITH). However, splicing factor genes-mutated cancers showed higher response rates to immune checkpoint inhibitors than splicing factor genes-wildtype cancers in six cancer cohorts. Single-cell data analysis confirmed that splicing factor genes mutations were associated with increased tumor stemness, proliferation capacity, PD-L1 expression, intratumor heterogeneity, and aneuploidy levels. Our data suggest that the mutation in key splicing factor genes correlates with unfavorable clinical outcomes and disease progression, genomic instability, anti-tumor immunosuppression, and increased immunotherapy response in pan-cancer. Thus, the splicing factor genes mutation is an adverse prognostic factor and a positive marker for immunotherapy response in cancer.
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Affiliation(s)
- Jiangti Luo
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China,Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China,Big Data Research Institute, China Pharmaceutical University, Nanjing, China
| | - Canping Chen
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China,Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China,Big Data Research Institute, China Pharmaceutical University, Nanjing, China
| | - Zhixian Liu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China,*Correspondence: Zhixian Liu, ; Xiaosheng Wang,
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China,Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China,Big Data Research Institute, China Pharmaceutical University, Nanjing, China,*Correspondence: Zhixian Liu, ; Xiaosheng Wang,
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Yoshimoto S, Chester N, Xiong A, Radaelli E, Wang H, Brillantes M, Gulendran G, Glassman P, Siegel DL, Mason NJ. Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors. MAbs 2023; 15:2287250. [PMID: 38047502 PMCID: PMC10793675 DOI: 10.1080/19420862.2023.2287250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/20/2023] [Indexed: 12/05/2023] Open
Abstract
PD-1 checkpoint inhibitors have revolutionized the treatment of patients with different cancer histologies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients show a dramatic clinical response to treatment. Despite intense biomarker discovery efforts, no single robust, prognostic correlation has emerged as a valid outcome predictor. Immune competent, pet dogs develop spontaneous tumors that share similar features to human cancers including chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and chemotherapeutic response. As such, they represent a valuable parallel patient population in which to investigate predictive biomarkers of checkpoint inhibition. However, the lack of a validated, non-immunogenic, canine anti-PD-1 antibody for pre-clinical use hinders this comparative approach and prevents potential clinical benefits of PD-1 blockade being realized in the veterinary clinic. To address this, fully canine single-chain variable fragments (scFvs) that bind canine (c)PD-1 were isolated from a comprehensive canine scFv phage display library. Lead candidates were identified that bound with high affinity to cPD-1 and inhibited its interaction with canine PD-L1 (cPD-L1). The lead scFv candidate re-formatted into a fully canine IgGD reversed the inhibitory effects of cPD-1:cPD-L1 interaction on canine chimeric antigen receptor (CAR) T cell function. In vivo administration showed no toxicity and revealed favorable pharmacokinetics for a reasonable dosing schedule. These results pave the way for clinical trials with anti-cPD-1 in canine cancer patients to investigate predictive biomarkers and combination regimens to inform human clinical trials and bring a promising checkpoint inhibitor into the veterinary armamentarium.
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Affiliation(s)
- Sho Yoshimoto
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Ailian Xiong
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Enrico Radaelli
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hong Wang
- Vetigenics LLC, B-Labs, Cira Center, Philadelphia, PA, USA
| | | | - Gayathri Gulendran
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Patrick Glassman
- Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA
| | - Don L. Siegel
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicola J. Mason
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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48
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Zhang Y, Li Y, Fu Q, Han Z, Wang D, Umar Shinge SA, Muluh TA, Lu X. Combined Immunotherapy and Targeted Therapies for Cancer Treatment: Recent Advances and Future Perspectives. Curr Cancer Drug Targets 2023; 23:251-264. [PMID: 36278447 DOI: 10.2174/1568009623666221020104603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/22/2022]
Abstract
The previous year's worldview for cancer treatment has advanced from general to more precise therapeutic approaches. Chemotherapies were first distinguished as the most reliable and brief therapy with promising outcomes in cancer patients. However, patients could also suffer from severe toxicities resulting from chemotherapeutic drug usage. An improved comprehension of cancer pathogenesis has led to new treatment choices, including tumor-targeted therapy and immunotherapy. Subsequently, cancer immunotherapy and targeted therapy give more hope to patients since their combination has tremendous therapeutic efficacy. The immune system responses are also initiated and modulated by targeted therapies and cytotoxic agents, which create the principal basis that when targeted therapies are combined with immunotherapy, the clinical outcomes are of excellent efficacy, as presented in this review. This review focuses on how immunotherapy and targeted therapy are applicable in cancer management and treatment. Also, it depicts promising therapeutic results with more extensive immunotherapy applications with targeted therapy. Further elaborate that immune system responses are also initiated and modulated by targeted therapies and cytotoxic agents, which create the principal basis that this combination therapy with immunotherapy can be of great outcome clinically.
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Affiliation(s)
- Yan Zhang
- Department of Oncology, The People's Hospital of Luzhou, 646000 Luzhou, Sichuan, P.R. China
| | - Yafei Li
- Department of Oncology, The People's Hospital of Luzhou, 646000 Luzhou, Sichuan, P.R. China
| | - Qiuxia Fu
- Department of Oncology, The People's Hospital of Luzhou, 646000 Luzhou, Sichuan, P.R. China
| | - Zhiqiang Han
- Department of Oncology, The People's Hospital of Luzhou, 646000 Luzhou, Sichuan, P.R. China
| | - Daijie Wang
- Department of Oncology, The People's Hospital of Luzhou, 646000 Luzhou, Sichuan, P.R. China
| | - Shafiu A Umar Shinge
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Sichuan, P.R. China
| | - Tobias Achu Muluh
- Department of Cardiovascular Surgery, The Affiliated Hospital of Southwest Medical University, Sichuan, P.R. China.,School of Medicine, Health Science Center, Shenzhen University, Shenzhen 518060, P.R. China
| | - Xiaohong Lu
- Department of Oncology, The People's Hospital of Luzhou, 646000 Luzhou, Sichuan, P.R. China
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49
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Yoshida T, Ogura G, Tanabe M, Hayashi T, Ohbayashi C, Azuma M, Kunisaki C, Akazawa Y, Ozawa S, Matsumoto S, Suzuki T, Mitoro A, Fukunaga T, Shimizu A, Fujimoto G, Yao T. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biol Ther 2022; 23:191-200. [PMID: 35220884 PMCID: PMC8890430 DOI: 10.1080/15384047.2022.2038002] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018–March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.
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Affiliation(s)
- Tsutomu Yoshida
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Go Ogura
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Mikiko Tanabe
- Division of Diagnostic Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Takuo Hayashi
- Department of Diagnostic Pathology, Main Hospital, Juntendo University, Tokyo, Japan
| | - Chiho Ohbayashi
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chikara Kunisaki
- Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, School of Medicine, Juntendo University, Tokyo, Japan
| | - Soji Ozawa
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Sohei Matsumoto
- Department of Surgery, Nara Medical University, Kashihara, Japan
| | - Takayoshi Suzuki
- Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Tokai University, Isehara, Japan
| | - Akira Mitoro
- Department of Gastroenterology, Nara Medical University, Kashihara, Japan
| | - Tetsu Fukunaga
- Department of Gastroenterology and Minimally Invasive Surgery, School of Medicine, Juntendo University, Tokyo, Japan
| | | | | | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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50
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Zhang Y, Li L, Chu F, Zhang L, Zhang L, Wu H, Li K. The tumor microenvironment in gastrointestinal adenocarcinomas revealed a prognostic and immunotherapeutic biomarker. Aging (Albany NY) 2022; 14:10171-10216. [PMID: 36585927 PMCID: PMC9831739 DOI: 10.18632/aging.204463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 12/22/2022] [Indexed: 12/31/2022]
Abstract
Accumulated evidence has elucidated that the tumor microenvironment (TME) is great of clinical significance in predicting survival outcomes and therapeutic efficacy. Nonetheless, few studies have investigated the prognostic and immunotherapeutic signature correlated with TME phenotypes in gastrointestinal adenocarcinomas (GIAC). Here, by estimating the TME pattern of immune infiltration and expression in over 1,000 GIAC patients, we revealed three TME subgroups and identified six key differential genes. To predict the TME phenotypes, TMEscore was established and validated to be an independent prognostic factor, where the high TMEscore was characterized by immune activation and response to immunotherapy and accompanied with favorable prognosis in GIAC. Furthermore, TMEscore was confirmed to predict prognosis and immunotherapeutic response in six datasets. In summary, depicting TME landscape of GIAC patients may be beneficial for interpreting survival and immunotherapeutic response, and provide new strategies for clinical treatment of GIAC.
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Affiliation(s)
- Yong Zhang
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China,Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province, Zhengzhou 450007, China,Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer, Zhengzhou 450007, China,Branch Center of Advanced Medical Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China
| | - Lu Li
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China,Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province, Zhengzhou 450007, China,Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer, Zhengzhou 450007, China
| | - Feifei Chu
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China,Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province, Zhengzhou 450007, China,Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer, Zhengzhou 450007, China
| | - Lei Zhang
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China,Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province, Zhengzhou 450007, China,Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer, Zhengzhou 450007, China
| | - Li Zhang
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China,Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province, Zhengzhou 450007, China,Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer, Zhengzhou 450007, China
| | - Huili Wu
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China,Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province, Zhengzhou 450007, China,Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer, Zhengzhou 450007, China
| | - Kunkun Li
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China,Medical Key Laboratory for Diagnosis and Treatment of Colorectal Cancer in Henan Province, Zhengzhou 450007, China,Zhengzhou Key Laboratory for Diagnosis, Treatment and Research of Colorectal Cancer, Zhengzhou 450007, China
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