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Binte Hanafi Z, Mei Y, Teo HY, Zhu Y, Yong Lionel CC, Chiu JW, Lu J, Liu H. Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment. Oncoimmunology 2025; 14:2451444. [PMID: 39803956 PMCID: PMC11730618 DOI: 10.1080/2162402x.2025.2451444] [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: 09/21/2024] [Revised: 12/26/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025] Open
Abstract
Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.
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Affiliation(s)
- Zuhairah Binte Hanafi
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yu Mei
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Huey Yee Teo
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ying Zhu
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chew Chin Yong Lionel
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jing Wen Chiu
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jinhua Lu
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Pan D, Li X, Qiao X, Wang Q. Immunosuppressive tumor microenvironment in pancreatic cancer: mechanisms and therapeutic targets. Front Immunol 2025; 16:1582305. [PMID: 40443678 PMCID: PMC12119487 DOI: 10.3389/fimmu.2025.1582305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 04/17/2025] [Indexed: 06/02/2025] Open
Abstract
Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. Conventional interventions including surgery, radiotherapy, and chemotherapy provide only modest survival benefits, underscoring an urgent need for more effective therapies. Although immunotherapy has revolutionized the management of several solid tumors, its clinical benefit in pancreatic cancer has so far been disappointing. Mounting evidence indicates that a highly immunosuppressive tumor microenvironment (TME), dominated by tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), drives immune evasion, tumor progression, metastasis, and chemoresistance through complex cytokine and chemokine networks. This review summarizes current knowledge of these immunosuppressive mechanisms and provides emerging strategies aimed at re-educating or depleting these cellular constituents to enhance the efficacy of immunotherapy in pancreatic cancer.
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Affiliation(s)
- Da Pan
- Department of Gastroenterology, Wenzhou Central Hospital, Wenzhou, China
- Department of Gastroenterology, The Dingli Clinical College of Wenzhou Medical University, Wenzhou, China
| | - Xinyue Li
- First College for Clinical Medicine, Xuzhou Medical University, Jiangsu, Xuzhou, China
| | - Xiao Qiao
- Department of Gastroenterology, The Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, China
| | - Qiqi Wang
- Department of Gastroenterology, Wenzhou Central Hospital, Wenzhou, China
- Department of Gastroenterology, The Dingli Clinical College of Wenzhou Medical University, Wenzhou, China
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Kaplan Z, Prezioso E, Jain A, Lavu H, Yeo CJ, Bowne WB, Nevler A. Clinical Implications of Mismatch Repair Deficiency in Pancreatic Ductal Adenocarcinoma. Cancer Med 2025; 14:e70960. [PMID: 40366030 PMCID: PMC12076359 DOI: 10.1002/cam4.70960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Pancreatic cancer is a highly aggressive and lethal disease, characterized by a limited response to chemotherapy and overall poor prognosis. Pancreatic cancers with a distinct mismatch repair deficiency, although relatively rare, have been shown to be associated with markedly better outcomes in comparison. Furthermore, whereas pancreatic cancers are generally unresponsive to current immunotherapy, this specific group of tumors has been shown to have a notable susceptibility to immune checkpoint inhibitors. AIMS In this review, we aim to summarize the relevant literature regarding mismatch-repair associated pancreatic cancers, the impacted biological mechanisms, and the resulting vulnerabilities for potential opportunistic immunotherapeutic treatment approaches. We will also review the current clinical studies assessing survival outcomes of mismatch repair deficient pancreatic cancers and ongoing clinical trials in this emerging field. RESULTS AND CONCLUSIONS Patients with dMMR/MSI-H pancreatic cancers harbor a distinct phenotype that has increased immune activation, greater responsiveness to immune checkpoint inhibitor therapy and better overall survival when compared to other pancreatic cancers. Although this molecular subtype makes up a small minority of cases, emerging data suggest immunotherapy may offer benefit to these patients.
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Affiliation(s)
- Zachary Kaplan
- Sidney Kimmel Medical CollegePhiladelphiaPennsylvaniaUSA
| | | | - Aditi Jain
- Jefferson Pancreatic, Biliary, and Related Cancer CenterSidney Kimmel Cancer CenterPhiladelphiaPennsylvaniaUSA
| | - Harish Lavu
- Jefferson Pancreatic, Biliary, and Related Cancer CenterSidney Kimmel Cancer CenterPhiladelphiaPennsylvaniaUSA
| | - Charles J. Yeo
- Jefferson Pancreatic, Biliary, and Related Cancer CenterSidney Kimmel Cancer CenterPhiladelphiaPennsylvaniaUSA
| | - Wilbur B. Bowne
- Jefferson Pancreatic, Biliary, and Related Cancer CenterSidney Kimmel Cancer CenterPhiladelphiaPennsylvaniaUSA
| | - Avinoam Nevler
- Jefferson Pancreatic, Biliary, and Related Cancer CenterSidney Kimmel Cancer CenterPhiladelphiaPennsylvaniaUSA
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Revilla SA, Frederiks CL, Prekovic S, Mocholi E, Kranenburg O, Coffer PJ. Tumor-derived colorectal cancer organoids induce a unique Treg cell population by directing CD4 + T cell differentiation. iScience 2025; 28:111827. [PMID: 39995881 PMCID: PMC11848486 DOI: 10.1016/j.isci.2025.111827] [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: 07/30/2024] [Revised: 11/22/2024] [Accepted: 01/13/2025] [Indexed: 02/26/2025] Open
Abstract
In colorectal cancer (CRC), increased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells correlate with tumor development, immunotherapy failure, and poor prognosis. To assess how CRC tumors directly modulate Treg cell differentiation, we developed an in vitro co-culture system using CD4+ T cells from Foxp3eGFP mice and CRC tumor-derived organoids. Co-culture resulted in a significant increase in Treg cell numbers. RNA-sequencing identified a distinct transcriptional profile of CRC organoid-induced Treg cells, with upregulation of genes associated with CRC Treg cells in vivo. High expression of genes upregulated in CRC organoid-induced Treg cells correlates with shorter progression-free intervals and overall survival in CRC patients. Human CRC organoids similarly induced Treg cells with enhanced suppressive capacity and upregulated genes linked to CRC Treg cells in vivo. This model provides insights into how CRC tumors modulate CD4+ T cell differentiation and can identify approaches to disrupt Treg cells and stimulate anti-tumor immunity.
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Affiliation(s)
- Sonia Aristin Revilla
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Cynthia L. Frederiks
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Stefan Prekovic
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Enric Mocholi
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Onno Kranenburg
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Paul J. Coffer
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
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Naei VY, Tubelleza R, Monkman J, Sadeghirad H, Donovan ML, Blick T, Wicher A, Bodbin S, Viratham A, Stad R, Basu S, Cooper C, Barnett C, O'Byrne K, Ladwa R, Warkiani ME, Hughes BGM, Kulasinghe A. Spatial interaction mapping of PD-1/PD-L1 in head and neck cancer reveals the role of macrophage-tumour barriers associated with immunotherapy response. J Transl Med 2025; 23:177. [PMID: 39939997 PMCID: PMC11818323 DOI: 10.1186/s12967-025-06186-y] [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: 10/22/2024] [Accepted: 01/29/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Mucosal head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, where the prognosis is poor due to the high rates of recurrence and metastasis. With approximately one million new cases projected in 2024, worldwide mortality of HNSCC is estimated to reach 50% of detected cases the same year. Patients with early-stage tumours showed a 50-60% five-year survival rate in the US. Immune checkpoint inhibitors (ICIs) have shown promising results in prolonging survival in a subset of patients with recurrent or metastatic disease. However, challenges remain, particularly the limited efficacy of PD-1/PD-L1 blockade therapies. PD-L1 protein expression has been shown to be limited in its predictive power for ICI therapies. Emerging evidence shows that intricate characterisation of the tumour microenvironment (TME) is fundamental to understand interacting cells. This study aims to bridge the gap in understanding the tumor microenvironment by identifying distinct spatial patterns of PD-1/PD-L1 interactions and their association with immunotherapy responses in head and neck squamous cell carcinoma (HNSCC). METHODS In this study, we sought to apply a more nuanced approach to understanding cellular interactions by mapping PD-1/PD-L1 interactions across whole-slide HNSCC tissue samples collected prior to ICI therapy. We used a combination of spatial proteomics (Akoya Biosciences) and an in situ proximity ligation assay (isPLA, Navinci Diagnostics) to visualise PD-1/PD-L1 interactions across cell types and cellular neighbourhoods within the tumour TME. RESULTS Our findings indicate the existence of isPLA+ PD-1/PD-L1 interactions between macrophages/CD3 T cell-enriched neighbourhoods and tumour cells at the tumour-stroma boundaries in ICI-resistant tumours. The presence of these dense macrophage-tumour layers, which are either absent or dispersed in responders, indicates a barrier that may restrict immune cell infiltration and promote immune escape mechanisms. In contrast, responders had abundant B and T cell aggregates, predominantly around the tumour edges linked to enhanced immune responses to ICI therapy and better clinical outcomes. CONCLUSION This study highlights the utility of isPLA in detecting distinct tumour-immune interactions within the TME, offering new cellular interaction metrics for stratifying and optimising immunotherapy strategies.
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Affiliation(s)
- Vahid Yaghoubi Naei
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Rafael Tubelleza
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - James Monkman
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - Habib Sadeghirad
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Meg L Donovan
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - Tony Blick
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | | | | | | | | | | | | | | | - Ken O'Byrne
- The Princess Alexandra Hospital, Brisbane, Australia
| | - Rahul Ladwa
- The Princess Alexandra Hospital, Brisbane, Australia
| | | | - Brett G M Hughes
- The Royal Brisbane and Women's Hospital, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Arutha Kulasinghe
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia.
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Huo MH, Adeerjiang Y, Abulitipu A, Khan U, Li XX, Zhang L, Tian Y, Jiang S, Xu CC, Chao XZ, Yang YF, Zhang JX, Du GL. Th17/Treg cell balance in patients with papillary thyroid carcinoma: a new potential biomarker and therapeutic target. Front Oncol 2024; 14:1325575. [PMID: 39534095 PMCID: PMC11554530 DOI: 10.3389/fonc.2024.1325575] [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: 10/21/2023] [Accepted: 10/10/2024] [Indexed: 11/16/2024] Open
Abstract
Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. The most effective treatment for PTC is surgical resection, and patients who undergo surgery have good survival outcomes, but some patients have distant metastasis or even multiorgan metastases at the time of initial diagnosis. Distant metastasis is associated with poorer prognosis and a higher mortality rate. Helper T lymphocyte 17 (Th17) cells and regulatory T lymphocytes (Tregs) play different roles in PTC, and the Th17/Treg balance is closely related to the progression of PTC. Th17 cells play anticancer roles, whereas Tregs play cancer-promoting roles. A Th17/Treg imbalance promotes tumor progression and accelerates invasive behaviors such as tumor metastasis. Th17/Treg homeostasis can be regulated by the TGF-β/IL-2 and IL-6 cytokine axes. Immune checkpoint inhibitors contribute to Treg/Th17 cell homeostasis. For PTC, monoclonal antibodies against CTLA-4, PD-1 and PD-L1 inhibit the activation of Tregs, reversing the Th17/Treg cell imbalance and providing a new option for the prevention and treatment of PTC. This article reviews the role of Tregs and Th17 cells in PTC and their potential targets, aiming to provide better treatment options for PTC.
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Affiliation(s)
- Meng-Han Huo
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Department of Gastroenterology and Endocrinology, Tianjin Haihe Hospital, Tianjin, China
| | - Yilinuer Adeerjiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Ayiguzhali Abulitipu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Umair Khan
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xin-Xi Li
- Department of Endocrine Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Lei Zhang
- Department of Endocrine Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Ye Tian
- Department of Endocrine Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Sheng Jiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Can-Can Xu
- First Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xian-Zhen Chao
- First Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Ye-Fan Yang
- First Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Jin-Xia Zhang
- First Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Guo-Li Du
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Department of Endocrinology, Bayingolin Mongolian Autonomous Prefecture People's Hospital, Kuerle, China
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Ju Y, Xu D, Liao MM, Sun Y, Bao WD, Yao F, Ma L. Barriers and opportunities in pancreatic cancer immunotherapy. NPJ Precis Oncol 2024; 8:199. [PMID: 39266715 PMCID: PMC11393360 DOI: 10.1038/s41698-024-00681-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 08/27/2024] [Indexed: 09/14/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents a fatal clinical challenge characterized by a dismal 5-year overall survival rate, primarily due to the lack of early diagnosis and limited therapeutic efficacy. Immunotherapy, a proven success in multiple cancers, has yet to demonstrate significant benefits in PDAC. Recent studies have revealed the immunosuppressive characteristics of the PDAC tumor microenvironment (TME), including immune cells with suppressive properties, desmoplastic stroma, microbiome influences, and PDAC-specific signaling pathways. In this article, we review recent advances in understanding the immunosuppressive TME of PDAC, TME differences among various mouse models of pancreatic cancer, and the mechanisms underlying resistance to immunotherapeutic interventions. Furthermore, we discuss the potential of targeting cancer cell-intrinsic pathways and TME components to sensitize PDAC to immune therapies, providing insights into strategies and future perspectives to break through the barriers in improving pancreatic cancer treatment.
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Affiliation(s)
- Yixin Ju
- Hubei Hongshan Laboratory, College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Shenzhen, Guangdong, 518000, China
| | - Dongzhi Xu
- Hubei Hongshan Laboratory, College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Shenzhen, Guangdong, 518000, China
| | - Miao-Miao Liao
- Hubei Hongshan Laboratory, College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Wen-Dai Bao
- Hubei Hongshan Laboratory, College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Fan Yao
- Hubei Hongshan Laboratory, College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Shenzhen, Guangdong, 518000, China.
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, Guangdong, 518000, China.
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
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Wang T, Sheng J, Wang X, Zhu M, Li S, Shen Y, Wu B. CXCL5 Promotes the Malignant Phenotype of Pancreatic Cancer and Is Associated With Immune Infiltration. Clin Med Insights Oncol 2024; 18:11795549241271691. [PMID: 39211563 PMCID: PMC11359438 DOI: 10.1177/11795549241271691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 06/27/2024] [Indexed: 09/04/2024] Open
Abstract
Background The significance of CXCL5 in pancreatic cancer is unclear, although it has been implicated in the malignant process of many different types of cancer. Research on the impact of CXCL5 on immune cell infiltration and the malignant phenotype of pancreatic cancer is needed. This study aimed to examine the connection between CXCL5 expression and immune cell infiltration and the malignant phenotype of pancreatic cancer. Methods Tissue samples and clinical information were collected from 90 patients with pancreatic cancer. Tumour tissues and adjacent tissues were made into a tissue microarray and stained for immunohistochemistry analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were performed to measure the expression level of CXCL5. CXCL5-overexpressing/CXCL5-knockdown cell lines were constructed via transfection for cytological experiments. CCK-8, cell apoptosis, cell cycle, cell invasion, and cell colony formation assays were used to detect the effect of CXCL5 on the malignant phenotype of pancreatic cancer cells. Finally, a mouse model of pancreatic cancer was constructed for in vivo verification. Results Compared with control cells, pancreatic cancer cells overexpressing CXCL5 exhibited increased proliferation, migration, and invasion but decreased apoptosis. Conversely, knockdown of CXCL5 did not enhance the malignant phenotype of pancreatic cancer cells. Spearman correlation analysis indicated that there was a significant negative correlation between CXCL5 levels and the CD8 IRS. However, there was a significant positive correlation between FOXP3 IRS and CXCL5 levels. Conclusions CXCL5 is highly expressed in pancreatic cancer and promotes the malignant phenotype of pancreatic cancer cells. CXCL5 is associated with immunosuppressive FOXP3 + T-cell infiltration, which facilitates the formation of an immunosuppressive microenvironment (with low CD8 + T-cell infiltration).
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Affiliation(s)
- Tao Wang
- Graduate School, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jian Sheng
- Department of Science and Education, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Xiaoguang Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Minyuan Zhu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Shijun Li
- Graduate School, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yiyu Shen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Bin Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
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Pratticò F, Garajová I. Focus on Pancreatic Cancer Microenvironment. Curr Oncol 2024; 31:4241-4260. [PMID: 39195299 PMCID: PMC11352508 DOI: 10.3390/curroncol31080316] [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: 06/16/2024] [Revised: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Pancreatic ductal adenocarcinoma remains one of the most lethal solid tumors due to its local aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. A robust connection between pancreatic cancer microenvironment and tumor progression exists, as well as resistance to current anticancer treatments. Pancreatic cancer has a complex tumor microenvironment, characterized by an intricate crosstalk between cancer cells, cancer-associated fibroblasts and immune cells. The complex composition of the tumor microenvironment is also reflected in the diversity of its acellular components, such as the extracellular matrix, cytokines, growth factors and secreted ligands involved in signaling pathways. Desmoplasia, the hallmark of the pancreatic cancer microenvironment, contributes by creating a dense and hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance and suppresses anti-tumor immune invasion. We discuss the complex crosstalk among tumor microenvironment components and explore therapeutic strategies and opportunities in pancreatic cancer research. Better understanding of the tumor microenvironment and its influence on pancreatic cancer progression could lead to potential novel therapeutic options, such as integration of immunotherapy and cytokine-targeted treatments.
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Affiliation(s)
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy;
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10
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Srivastava P, Yadav VK, Chang TH, Su ECY, Lawal B, Wu ATH, Huang HS. In-silico analysis of TMEM2 as a pancreatic adenocarcinoma and cancer-associated fibroblast biomarker, and functional characterization of NSC777201, for targeted drug development. Am J Cancer Res 2024; 14:3010-3035. [PMID: 39005682 PMCID: PMC11236765 DOI: 10.62347/chxd6134] [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: 01/07/2024] [Accepted: 05/13/2024] [Indexed: 07/16/2024] Open
Abstract
Pancreatic adenocarcinoma (PAAD), known as one of the deadliest cancers, is characterized by a complex tumor microenvironment, primarily comprised of cancer-associated fibroblasts (CAFs) in the extracellular matrix. These CAFs significantly alter the matrix by interacting with hyaluronic acid (HA) and the enzyme hyaluronidase, which degrades HA - an essential process for cancer progression and spread. Despite the critical role of this interaction, the specific functions of CAFs and hyaluronidase in PAAD development are not fully understood. Our study investigates this interaction and assesses NSC777201, a new anti-cancer compound targeting hyaluronidase. This research utilized computational methods to analyze gene expression data from the Gene Expression Omnibus (GEO) database, specifically GSE172096, comparing gene expression profiles of cancer-associated and normal fibroblasts. We conducted in-house sequencing of pancreatic cancer cells treated with NSC777201 to identify differentially expressed genes (DEGs) and performed functional enrichment and pathway analysis. The identified DEGs were further validated using the TCGA-PAAD and Human Protein Atlas (HPA) databases for their diagnostic, prognostic, and survival implications, accompanied by Ingenuity Pathway Analysis (IPA) and molecular docking of NSC777201, in-vitro, and preclinical in-vivo validations. The result revealed 416 DEGs associated with CAFs and 570 DEGs related to NSC777201 treatment, with nine overlapping DEGs. A key finding was the transmembrane protein TMEM2, which strongly correlated with FAP, a CAF marker, and was associated with higher-risk groups in PAAD. NSC777201 treatment showed inhibition of TMEM2, validated by rescue assay, indicating the importance of targeting TMEM2. Further analyses, including IPA, demonstrated that NSC777201 regulates CAF cell senescence, enhancing its therapeutic potential. Both in-vitro and in-vivo studies confirmed the inhibitory effect of NSC777201 on TMEM2 expression, reinforcing its role in targeting PAAD. Therefore, TMEM2 has been identified as a theragnostic biomarker in PAAD, influenced by CAF activity and HA accumulation. NSC777201 exhibits significant potential in targeting and potentially reversing critical processes in PAAD progression, demonstrating its efficacy as a promising therapeutic agent.
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Affiliation(s)
- Prateeti Srivastava
- The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical UniversityTaipei 110, Taiwan
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical UniversityTaipei 110, Taiwan
| | - Vijesh Kumar Yadav
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho HospitalNew Taipei 23561, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei 110, Taiwan
| | - Tzu-Hao Chang
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical UniversityTaipei 110, Taiwan
- Clinical Big Data Research Center, Taipei Medical University HospitalTaipei 110, Taiwan
| | - Emily Chia-Yu Su
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical UniversityTaipei 110, Taiwan
| | - Bashir Lawal
- UPMC Hillman Cancer Center, University of PittsburghPittsburgh, PA 15232, USA
- Department of Pathology, University of PittsburghPittsburgh, PA 15213, USA
| | - Alexander TH Wu
- The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical UniversityTaipei 110, Taiwan
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical UniversityTaipei 110, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical CenterTaipei 114, Taiwan
- The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical UniversityTaipei 110, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical UniversityTaipei 110, Taiwan
- Clinical Research Center, Taipei Medical University Hospital, Taipei Medical UniversityTaipei 11031, Taiwan
| | - Hsu-Shan Huang
- Graduate Institute of Medical Sciences, National Defense Medical CenterTaipei 114, Taiwan
- Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityTaipei 110, Taiwan
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Academia SinicaTaipei 11031, Taiwan
- School of Pharmacy, National Defense Medical CenterTaipei 11490, Taiwan
- PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical UniversityTaipei 11031, Taiwan
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11
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Zou X, Shen J, Yong X, Diao Y, Zhang L. The causal effects of immune cells on pancreatic cancer: A 2‑sample Mendelian randomization study. Medicine (Baltimore) 2024; 103:e37797. [PMID: 38640310 PMCID: PMC11029941 DOI: 10.1097/md.0000000000037797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/24/2024] [Accepted: 03/14/2024] [Indexed: 04/21/2024] Open
Abstract
Leveraging publicly available genetic datasets, we conducted a comprehensive 2-sample Mendelian randomization (MR) analysis to explore the causal links between 731 immunophenotypes and the risk of pancreatic cancer (PC). To ensure the robustness of our findings, extensive sensitivity analyses were performed, evaluating stability, heterogeneity, and potential horizontal pleiotropy. Our analysis pinpointed 24 immunophenotypes significantly associated with the risk of PC. Notably, phenotypes such as CD4+ CD8dim %leukocyte (OR = 0.852, 95% CI = 0.729-0.995, P = .0430) and HLA DR+ CD4+ AC (OR = 0.933, 95% CI = 0.883-0.986) in TBNK were inversely correlated with PC risk. Conversely, phenotypes like CD28 on CD45RA- CD4 non-Treg (OR = 1.155, 95% CI = 1.028-1.297, P = .016) and CD25 on activated Treg (OR = 1.180, 95% CI = 1.014-1.374, P = .032) in Treg cells, among others, exhibited a positive correlation. These insights offer a valuable genetic perspective that could guide future clinical research in this area.
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Affiliation(s)
- Xinyun Zou
- Department of Oncology, People’s Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Jinlan Shen
- Department of Medical Laboratory, People’s Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Xiaomei Yong
- Department of Oncology, People’s Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Yong Diao
- Department of Oncology, People’s Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Ling Zhang
- Department of Oncology, People’s Liberation Army The General Hospital of Western Theater Command, Chengdu, China
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12
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Silva LGDO, Lemos FFB, Luz MS, Rocha Pinheiro SL, Calmon MDS, Correa Santos GL, Rocha GR, de Melo FF. New avenues for the treatment of immunotherapy-resistant pancreatic cancer. World J Gastrointest Oncol 2024; 16:1134-1153. [PMID: 38660642 PMCID: PMC11037047 DOI: 10.4251/wjgo.v16.i4.1134] [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: 12/29/2023] [Revised: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
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Affiliation(s)
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Mariana dos Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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13
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Wang J, Gai J, Zhang T, Niu N, Qi H, Thomas DL, Li K, Xia T, Rodriguez C, Parkinson R, Durham J, McPhaul T, Narang AK, Anders RA, Osipov A, Wang H, He J, Laheru DA, Herman JM, Lee V, Jaffee EM, Thompson ED, Zhu Q, Zheng L. Neoadjuvant radioimmunotherapy in pancreatic cancer enhances effector T cell infiltration and shortens their distances to tumor cells. SCIENCE ADVANCES 2024; 10:eadk1827. [PMID: 38324679 PMCID: PMC10849596 DOI: 10.1126/sciadv.adk1827] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 01/08/2024] [Indexed: 02/09/2024]
Abstract
Radiotherapy is hypothesized to have an immune-modulating effect on the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) to sensitize it to anti-PD-1 antibody (a-PD-1) treatment. We collected paired pre- and posttreatment specimens from a clinical trial evaluating combination treatment with GVAX vaccine, a-PD-1, and stereotactic body radiation (SBRT) following chemotherapy for locally advanced PDACs (LAPC). With resected PDACs following different neoadjuvant therapies as comparisons, effector cells in PDACs were found to skew toward a more exhausted status in LAPCs following chemotherapy. The combination of GVAX/a-PD-1/SBRT drives TME to favor antitumor immune response including increased densities of GZMB+CD8+ T cells, TH1, and TH17, which are associated with longer survival, however increases immunosuppressive M2-like tumor-associated macrophages (TAMs). Adding SBRT to GVAX/a-PD-1 shortens the distances from PD-1+CD8+ T cells to tumor cells and to PD-L1+ myeloid cells, which portends prolonged survival. These findings have guided the design of next radioimmunotherapy studies by targeting M2-like TAM in PDACs.
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Affiliation(s)
- Junke Wang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jessica Gai
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Tengyi Zhang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Nan Niu
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Hanfei Qi
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Quantitative Sciences Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Dwayne L. Thomas
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Keyu Li
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Tao Xia
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Christina Rodriguez
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Rose Parkinson
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jennifer Durham
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Thomas McPhaul
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Amol K. Narang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Robert A. Anders
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Arsen Osipov
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Hao Wang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Quantitative Sciences Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jin He
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Daniel A. Laheru
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Joseph M. Herman
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Northwell Health System, New Hyde Park, NY, 11042, USA
| | - Valerie Lee
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Elizabeth M. Jaffee
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Elizabeth D. Thompson
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Qingfeng Zhu
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Lei Zheng
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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14
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Joseph AM, Al Aiyan A, Al-Ramadi B, Singh SK, Kishore U. Innate and adaptive immune-directed tumour microenvironment in pancreatic ductal adenocarcinoma. Front Immunol 2024; 15:1323198. [PMID: 38384463 PMCID: PMC10879611 DOI: 10.3389/fimmu.2024.1323198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 01/11/2024] [Indexed: 02/23/2024] Open
Abstract
One of the most deadly and aggressive cancers in the world, pancreatic ductal adenocarcinoma (PDAC), typically manifests at an advanced stage. PDAC is becoming more common, and by the year 2030, it is expected to overtake lung cancer as the second greatest cause of cancer-related death. The poor prognosis can be attributed to a number of factors, including difficulties in early identification, a poor probability of curative radical resection, limited response to chemotherapy and radiotherapy, and its immunotherapy resistance. Furthermore, an extensive desmoplastic stroma that surrounds PDAC forms a mechanical barrier that prevents vascularization and promotes poor immune cell penetration. Phenotypic heterogeneity, drug resistance, and immunosuppressive tumor microenvironment are the main causes of PDAC aggressiveness. There is a complex and dynamic interaction between tumor cells in PDAC with stromal cells within the tumour immune microenvironment. The immune suppressive microenvironment that promotes PDAC aggressiveness is contributed by a range of cellular and humoral factors, which itself are modulated by the cancer. In this review, we describe the role of innate and adaptive immune cells, complex tumor microenvironment in PDAC, humoral factors, innate immune-mediated therapeutic advances, and recent clinical trials in PDAC.
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Affiliation(s)
- Ann Mary Joseph
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ahmad Al Aiyan
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
| | - Basel Al-Ramadi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Shiv K. Singh
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, Goettingen, Germany
| | - Uday Kishore
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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15
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Dabiri R, Rashid MU, Khan OS, Jehanzeb S, Alomari M, Zafar H, Zahid E, Rahman AU, Karam A, Ahmad S. Immune modulators for pancreatic ductal adenocarcinoma therapy. IMMUNE LANDSCAPE OF PANCREATIC CANCER DEVELOPMENT AND DRUG RESISTANCE 2024:103-129. [DOI: 10.1016/b978-0-443-23523-8.00021-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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Ashina S, Masuda A, Yamakawa K, Hamada T, Tsujimae M, Tanaka T, Toyama H, Sofue K, Shiomi H, Sakai A, Kobayashi T, Abe S, Gonda M, Masuda S, Inomata N, Uemura H, Kohashi S, Nagao K, Harada Y, Miki M, Juri N, Irie Y, Kanzawa M, Itoh T, Inoue J, Imai T, Fukumoto T, Kodama Y. A comprehensive analysis of tumor-stromal collagen in relation to pathological, molecular, and immune characteristics and patient survival in pancreatic ductal adenocarcinoma. J Gastroenterol 2023; 58:1055-1067. [PMID: 37477731 PMCID: PMC10522520 DOI: 10.1007/s00535-023-02020-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 07/03/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND Abundant collagen deposition is a hallmark of pancreatic ductal adenocarcinomas (PDACs). This study clarified the interactive relationship between tumor-stromal collagen, molecular and immune characteristics, and tumor pr ogression in human PDAC. METHODS We performed a comprehensive examination using an integrative molecular pathological epidemiology database on 169 cases with resected PDAC . The amount of tumor-stromal collagen was quantified through digital imaging analysis for Elastica van Gieson-stained whole-section tumor slides. We analyzed the association of tumor-stromal collagen with gene alterations (KRAS, TP53, CDKN2A/p16, and SMAD4), immune parameters (CD4+ tumor-infiltrating lymphocytes [TILs], CD8+ TILs, FOXP3+ TILs, and tertiary lymphoid structures), and patient prognosis. RESULTS Low amounts of tumor-stromal collagen were associated with poor differentiation (multivariable OR = 3.82, 95%CI = 1.41-12.2, P = 0.008) and CDKN2A/p16 alteration (OR [95%CI] = 2.06 [1.08-4.02], P = 0.03). Tumors with low collagen levels had shorter overall survival (HR [95%CI] = 2.38 [1.59-3.56], P < 0.0001). In the S-1 and gemcitabine (GEM) treatment groups, low tumor-stromal collagen was linked to poor prognosis of patients with PDAC (S-1 group: multivariable HR [95%CI] = 2.76 [1.36-5.79], P = 0.005; GEM group: multivariate HR [95%CI] = 2.91 [1.34-6.71], P = 0.007). Additionally, low amounts of tumor-stromal collagen were also linked to low levels of CD4+ TILs (P = 0.046), CD8+ TILs (P = 0.09), and tertiary lymphoid structures (P = 0.001). CONCLUSIONS Tumor-stromal collagen deposition may play a crucial role in modulating tumor-immune microenvironment and determining response to adjuvant chemotherapy and patient survival outcomes.
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Affiliation(s)
- Shigeto Ashina
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Atsuhiro Masuda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
| | - Kohei Yamakawa
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Masahiro Tsujimae
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Takeshi Tanaka
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Hirochika Toyama
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Keitaro Sofue
- Department of Radiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Hideyuki Shiomi
- Division of Gastroenterology and Hepatobiliary and Pancreatic Diseases, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 650-0017, Japan
| | - Arata Sakai
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Takashi Kobayashi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shohei Abe
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Masanori Gonda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shigeto Masuda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Noriko Inomata
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Hisahiro Uemura
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shinya Kohashi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Kae Nagao
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yoshiyuki Harada
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Mika Miki
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Noriko Juri
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yosuke Irie
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Maki Kanzawa
- Division of Diagnostic Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Tomoo Itoh
- Division of Diagnostic Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Jun Inoue
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Toshio Imai
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Takumi Fukumoto
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
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Roy AM, George S. Emerging resistance vs. losing response to immune check point inhibitors in renal cell carcinoma: two differing phenomena. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:642-655. [PMID: 37842239 PMCID: PMC10571056 DOI: 10.20517/cdr.2023.47] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 08/27/2023] [Accepted: 09/16/2023] [Indexed: 10/17/2023]
Abstract
The introduction of immune checkpoint inhibitor (ICI) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and has dramatically improved the outcomes of patients. The use of monotherapy or combinations of ICIs targeting PD-1/PD-L1 and CTLA-4, as well as the addition of ICIs with tyrosine kinase inhibitors, has significantly enhanced the overall survival of mRCC patients. Despite these promising results, there remains a subset of patients who either do not respond to treatment (primary resistance) or develop resistance to therapy over time (acquired resistance). Understanding the mechanisms underlying the development of resistance to ICI treatment is crucial in the management of mRCC, as they can be used to identify new targets for innovative therapeutic strategies. Currently, there is an unmet need to develop new predictive and prognostic biomarkers that can aid in the development of personalized treatment options for mRCC patients. In this review, we summarize several mechanisms of ICI resistance in RCC, including alterations in tumor microenvironment, upregulation of alternative immune checkpoint pathways, and genetic and epigenetic changes. Additionally, we highlight potential strategies that can be used to overcome resistance, such as combination therapy, targeted therapy, and immune modulation.
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Affiliation(s)
| | - Saby George
- Division of Hematology and Oncology, Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
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18
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Zou X, Guan C, Gao J, Shi W, Cui Y, Zhong X. Tertiary lymphoid structures in pancreatic cancer: a new target for immunotherapy. Front Immunol 2023; 14:1222719. [PMID: 37529035 PMCID: PMC10388371 DOI: 10.3389/fimmu.2023.1222719] [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: 05/15/2023] [Accepted: 06/26/2023] [Indexed: 08/03/2023] Open
Abstract
Pancreatic cancer (PC) is extremely malignant and shows limited response to available immunotherapies due to the hypoxic and immunosuppressive nature of its tumor microenvironment (TME). The aggregation of immune cells (B cells, T cells, dendritic cells, etc.), which is induced in various chronic inflammatory settings such as infection, inflammation, and tumors, is known as the tertiary lymphoid structure (TLS). Several studies have shown that TLSs can be found in both intra- and peritumor tissues of PC. The role of TLSs in peritumor tissues in tumors remains unclear, though intratumoral TLSs are known to play an active role in a variety of tumors, including PC. The formation of intratumoral TLSs in PC is associated with a good prognosis. In addition, TLSs can be used as an indicator to assess the effectiveness of treatment. Targeted induction of TLS formation may become a new avenue of immunotherapy for PC. This review summarizes the formation, characteristics, relevant clinical outcomes, and clinical applications of TLSs in the pancreatic TME. We aim to provide new ideas for future immunotherapy of PC.
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Affiliation(s)
- Xinlei Zou
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Canghai Guan
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jianjun Gao
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wujiang Shi
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunfu Cui
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiangyu Zhong
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
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19
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Heiduk M, Klimova A, Reiche C, Digomann D, Beer C, Aust DE, Distler M, Weitz J, Seifert AM, Seifert L. TIGIT Expression Delineates T-cell Populations with Distinct Functional and Prognostic Impact in Pancreatic Cancer. Clin Cancer Res 2023; 29:2638-2650. [PMID: 37140899 PMCID: PMC10345964 DOI: 10.1158/1078-0432.ccr-23-0258] [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: 01/28/2023] [Revised: 04/05/2023] [Accepted: 05/01/2023] [Indexed: 05/05/2023]
Abstract
PURPOSE Immunotherapy has led to a fundamental shift in the treatment of several cancers. However, its efficacy in pancreatic ductal adenocarcinoma (PDAC) is limited. Understanding the expression of inhibitory immune checkpoint receptors (ICR) by intratumoral T cells may help to unravel their involvement in insufficient T-cell-mediated antitumor immunity. EXPERIMENTAL DESIGN Using multicolor flow cytometry, we analyzed circulating and intratumoral T cells from blood (n = 144) and matched tumor samples (n = 107) of patients with PDAC. We determined the expression of programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) by CD8+ T-cells, conventional CD4+ T-cells (Tconv) and regulatory T cells (Treg) and their association with T-cell differentiation, tumor reactivity, and cytokine expression. A comprehensive follow-up was used to determine their prognostic value. RESULTS Intratumoral T cells were characterized by increased PD-1 and TIGIT expression. Both markers delineated distinct T-cell subpopulations. PD-1+TIGIT- T cells highly expressed proinflammatory cytokines and markers of tumor reactivity (CD39, CD103), whereas TIGIT expression was linked to antiinflammatory and exhausted phenotypes. In addition, the enhanced presence of intratumoral PD-1+TIGIT- Tconv was associated with improved clinical outcomes, while high ICR expression on blood T cells was a significant hazard for overall survival (OS). CONCLUSIONS Our results uncover the association between ICR expression and T-cell functionality. PD-1 and TIGIT characterized intratumoral T cells with highly divergent phenotypes linked to clinical outcomes, further underscoring the relevance of TIGIT for immunotherapeutic approaches in PDAC. The prognostic value of ICR expression in patient blood may be a valuable tool for patient stratification.
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Affiliation(s)
- Max Heiduk
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Anna Klimova
- National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Charlotte Reiche
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - David Digomann
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Carolin Beer
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Daniela E. Aust
- Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Biobank Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Marius Distler
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Adrian M. Seifert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lena Seifert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Else Kröner Clinician Scientist Professor for Translational Tumor Immunological Research, Dresden, Germany
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20
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Wen C, Zhang L, Yang Y, Jin Y, Ren D, Zhang Z, Zou S, Li F, Sun H, Jin J, Lu X, Xie J, Cheng D, Xu Z, Chen H, Mao B, Zhang J, Wang J, Deng X, Peng C, Li H, Jiang C, Lin L, Zhang H, Chen H, Shen B, Zhan Q. Specific human leukocyte antigen class I genotypes predict prognosis in resected pancreatic adenocarcinoma: a retrospective cohort study. Int J Surg 2023; 109:1941-1952. [PMID: 37026827 PMCID: PMC10389500 DOI: 10.1097/js9.0000000000000264] [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: 08/05/2022] [Accepted: 01/26/2023] [Indexed: 04/08/2023]
Abstract
BACKGROUND Patients with resected pancreatic adenocarcinoma (PAAD) often experience short-term relapse and dismal survival, suggesting an urgent need to develop predictive and/or prognostic biomarkers for these populations. Given the potential associations of the human leukocyte antigen class I ( HLA -I) genotype with oncogenic mutational profile and immunotherapy efficacy, we aimed to assess whether differential HLA -I genotype could predict the postoperative outcomes in resected PAAD patients. MATERIALS AND METHODS HLA -I ( A , B , and C ) genotyping and somatic variants of 608 Chinese PAAD patients were determined by targeted next-generation sequencing of matched blood cells and tumor tissues. HLA - A / B alleles were classified with the available definition of 12 supertypes. The Kaplan-Meier curves of disease-free survival (DFS) and multivariable Cox proportional-hazards regression analyses were performed to determine the survival difference in 226 selected patients with radical resection. Early-stage (I-II) patients constituted the majority (82%, 185/226) and some stage I-II individuals with high-quality tumor samples were analyzed by RNA-sequencing to examine immunophenotypes. RESULTS Patients with HLA-A02 + B62 + B44 - had significantly shorter DFS (median, 239 vs. 410 days; hazard ratio=1.65, P =0.0189) than patients without this genotype. Notably, stage I-II patients carrying HLA-A02 + B62 + B44 - had sharply shorter DFS than those without HLA-A02 + B62 + B44 - (median, 237 vs. 427 days; hazard ratio=1.85, P =0.007). Multivariate analysis revealed that HLA-A02 + B62 + B44 - was associated with significantly inferior DFS ( P =0.014) in stage I-II patients but not in stage III patients. Mechanistically, HLA-A02 + B62 + B44 - patients were associated with a high rate of KRAS G12D and TP53 mutations, lower HLA-A expression, and less inflamed T-cell infiltration. CONCLUSION The current results suggest that a specific combination of germline HLA-A02/B62/B44 supertype, HLA-A02 + B62 + B44 - , was a potential predictor for DFS in early-stage PAAD patients after surgery.
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Affiliation(s)
- Chenlei Wen
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Lei Zhang
- Genecast Biotechnology Co. Ltd, Wuxi, Jiangsu Province
| | - Ying Yang
- Genecast Biotechnology Co. Ltd, Wuxi, Jiangsu Province
| | - Yangbing Jin
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Dandan Ren
- Genecast Biotechnology Co. Ltd, Wuxi, Jiangsu Province
| | - Zehui Zhang
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Siyi Zou
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Fanlu Li
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Huaibo Sun
- Genecast Biotechnology Co. Ltd, Wuxi, Jiangsu Province
| | - Jiabin Jin
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Xiongxiong Lu
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Junjie Xie
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Dongfeng Cheng
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Zhiwei Xu
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Huan Chen
- Genecast Biotechnology Co. Ltd, Wuxi, Jiangsu Province
| | - Beibei Mao
- Genecast Biotechnology Co. Ltd, Wuxi, Jiangsu Province
| | - Jun Zhang
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Jiancheng Wang
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Xiaxing Deng
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Chenghong Peng
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Hongwei Li
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Cen Jiang
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Lin Lin
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Henghui Zhang
- Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hao Chen
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Baiyong Shen
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
| | - Qian Zhan
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
- State Key Laboratory of Oncogenes and Related Genes, National Research Center for Translational Medicine (Shanghai), Shanghai
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21
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Sun G, Yang Z, Fang K, Xiong Y, Tu S, Yi S, Xiao W. Distribution characteristics and clinical significance of infiltrating T cells in the tumor microenvironment of pancreatic cancer. Oncol Lett 2023; 25:261. [PMID: 37205920 PMCID: PMC10189847 DOI: 10.3892/ol.2023.13847] [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: 07/28/2022] [Accepted: 03/24/2023] [Indexed: 05/21/2023] Open
Abstract
Tumor-infiltrating lymphocytes (TILs) are important components of the tumor microenvironment (TME). However, the distribution characteristics of TILs and their significance in pancreatic cancer (PC) remain largely unexplored. The levels of TILs, including the total number of T cells, cluster of differentiation (CD)4+ T cells, CD8+ cytotoxic T lymphocytes (CTLs), regulatory T-cells (Tregs), programmed cell death protein 1+ T cells and programmed cell death ligand 1 (PD-L1)+ T cells, in the TME of patients with PC were detected using multiple fluorescence immunohistochemistry. The associations between the number of TILs and the clinicopathological characteristics were investigated using χ2 tests. In addition, Kaplan-Meier survival and Cox regression analyses were used to assess the prognostic value of these TIL types. Compared with paracancerous tissues, in PC tissues, the proportions of total T cells, CD4+ T cells and CD8+ CTLs were markedly decreased, while those of Tregs and PD-L1+ T cells were significantly increased. The levels of CD4+ T cell and CD8+ CTL infiltrates were inversely associated with tumor differentiation. Higher infiltrates of Tregs and PD-L1+ T cells were closely associated with advanced N and TNM stages. It is important to note that the infiltrates of total T cells, CD4+ T cells, Tregs and PD-L1+ T cells in the TME were independent risk factors for the prognosis of PC. PC was characterized by an immunosuppressive TME with a decrease in the number of CD4+ T cells and CD8+ CTLs, and an increase in the number of Tregs and PD-L1+ T cells. Overall, the number of total T cells, CD4+ T cells, Tregs and PD-L1+ T cells in the TME was a potential predictive marker for the prognosis of PC.
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Affiliation(s)
- Gen Sun
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhengjiang Yang
- Department of General Surgery, The Affiliated Hospital of Jiujiang College, Jiujiang, Jiangxi 332001, P.R. China
| | - Kang Fang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yuanpeng Xiong
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shuju Tu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Siqing Yi
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Weidong Xiao
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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22
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Zhang H, AbdulJabbar K, Moore DA, Akarca A, Enfield KS, Jamal-Hanjani M, Raza SEA, Veeriah S, Salgado R, McGranahan N, Le Quesne J, Swanton C, Marafioti T, Yuan Y. Spatial Positioning of Immune Hotspots Reflects the Interplay between B and T Cells in Lung Squamous Cell Carcinoma. Cancer Res 2023; 83:1410-1425. [PMID: 36853169 PMCID: PMC10152235 DOI: 10.1158/0008-5472.can-22-2589] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 01/05/2023] [Accepted: 02/24/2023] [Indexed: 03/01/2023]
Abstract
Beyond tertiary lymphoid structures, a significant number of immune-rich areas without germinal center-like structures are observed in non-small cell lung cancer. Here, we integrated transcriptomic data and digital pathology images to study the prognostic implications, spatial locations, and constitution of immune rich areas (immune hotspots) in a cohort of 935 patients with lung cancer from The Cancer Genome Atlas. A high intratumoral immune hotspot score, which measures the proportion of immune hotspots interfacing with tumor islands, was correlated with poor overall survival in lung squamous cell carcinoma but not in lung adenocarcinoma. Lung squamous cell carcinomas with high intratumoral immune hotspot scores were characterized by consistent upregulation of B-cell signatures. Spatial statistical analyses conducted on serial multiplex IHC slides further revealed that only 4.87% of peritumoral immune hotspots and 0.26% of intratumoral immune hotspots were tertiary lymphoid structures. Significantly lower densities of CD20+CXCR5+ and CD79b+ B cells and less diverse immune cell interactions were found in intratumoral immune hotspots compared with peritumoral immune hotspots. Furthermore, there was a negative correlation between the percentages of CD8+ T cells and T regulatory cells in intratumoral but not in peritumoral immune hotspots, with tertiary lymphoid structures excluded. These findings suggest that the intratumoral immune hotspots reflect an immunosuppressive niche compared with peritumoral immune hotspots, independent of the distribution of tertiary lymphoid structures. A balance toward increased intratumoral immune hotspots is indicative of a compromised antitumor immune response and poor outcome in lung squamous cell carcinoma. SIGNIFICANCE Intratumoral immune hotspots beyond tertiary lymphoid structures reflect an immunosuppressive microenvironment, different from peritumoral immune hotspots, warranting further study in the context of immunotherapies.
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Affiliation(s)
- Hanyun Zhang
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Khalid AbdulJabbar
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - David A. Moore
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom
- Department of Cellular Pathology, University College London Hospitals, London, United Kingdom
| | - Ayse Akarca
- Department of Cellular Pathology, University College London Hospitals, London, United Kingdom
| | - Katey S.S. Enfield
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Mariam Jamal-Hanjani
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom
- Department of Oncology, University College London Hospitals, London, United Kingdom
- Cancer Metastasis Lab, University College London Cancer Institute, London, United Kingdom
| | - Shan E. Ahmed Raza
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Selvaraju Veeriah
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom
| | | | - Nicholas McGranahan
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom
| | - John Le Quesne
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- NHS Greater Glasgow and Clyde Pathology Department, Queen Elizabeth University Hospital, London, United Kingdom
| | - Charles Swanton
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, United Kingdom
- Department of Oncology, University College London Hospitals, London, United Kingdom
| | - Teresa Marafioti
- Department of Cellular Pathology, University College London Hospitals, London, United Kingdom
| | - Yinyin Yuan
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
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23
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Boucher Y, Posada JM, Subudhi S, Kumar AS, Rosario SR, Gu L, Kumra H, Mino-Kenudson M, Talele NP, Duda DG, Fukumura D, Wo JY, Clark JW, Ryan DP, Fernandez-Del Castillo C, Hong TS, Pittet MJ, Jain RK. Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer. Clin Cancer Res 2023; 29:1605-1619. [PMID: 36749873 PMCID: PMC10106451 DOI: 10.1158/1078-0432.ccr-22-1630] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 12/31/2022] [Accepted: 02/03/2023] [Indexed: 02/09/2023]
Abstract
PURPOSE Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant LOS on the tumor microenvironment. EXPERIMENTAL DESIGN We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733), or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients. RESULTS In comparison with FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with dendritic cell (DC) and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel-related genes for those treated with LOS+FFX+CRT. Furthermore, LOS induced specific changes in circulating levels of IL-8, sTie2, and TGF-β. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Finally, patients with a complete/near complete pathologic response in the LOS+FFX+CRT-treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3), and increased CD8+ T cells in pancreatic ductal adenocarcinoma lesions. CONCLUSIONS Adding LOS to FFX+CRT reduced pro-invasion and immunosuppression-related genes, which were associated with improved OS in patients with LAPC. Lesions from responders in the LOS+FFX+CRT-treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that LOS may potentiate the benefit of FFX+CRT by reducing immunosuppression.
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Affiliation(s)
- Yves Boucher
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Jessica M. Posada
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Pathology, Brigham and Women’s Hospital, Boston, University of Geneva, CH-1211 Geneva, Switzerland
| | - Sonu Subudhi
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Ashwin S. Kumar
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
- Harvard–MIT Division of Health Sciences and Technology, Cambridge, University of Geneva, CH-1211 Geneva, Switzerland
| | - Spencer R. Rosario
- Department of Biostatistics and Bioinformatics, University of Geneva, CH-1211 Geneva, Switzerland
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, University of Geneva, CH-1211 Geneva, Switzerland
| | - Liqun Gu
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Heena Kumra
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Mari Mino-Kenudson
- Department of Pathology, University of Geneva, CH-1211 Geneva, Switzerland
| | - Nilesh P. Talele
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Dan G. Duda
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Dai Fukumura
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Jennifer Y. Wo
- Department of Radiation Oncology, University of Geneva, CH-1211 Geneva, Switzerland
| | - Jeffrey W. Clark
- Department of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - David P. Ryan
- Department of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | | | - Theodore S. Hong
- Department of Radiation Oncology, University of Geneva, CH-1211 Geneva, Switzerland
| | - Mikael J. Pittet
- Department of Pathology and Immunology, University of Geneva, CH-1211 Geneva, Switzerland
- Ludwig Institute for Cancer Research, 1005 Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - Rakesh K. Jain
- Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston
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24
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Tulyte S, Characiejus D, Matuzeviciene R, Janiulioniene A, Radzevicius M, Jasiunaite E, Zvirblis T, Sileikis A. Prognostic value of circulating T-lymphocyte subsets in advanced pancreatic cancer patients treated with mFOLFIRINOX or gemcitabine. Int Immunopharmacol 2023; 115:109722. [PMID: 37724957 DOI: 10.1016/j.intimp.2023.109722] [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: 11/26/2022] [Revised: 01/08/2023] [Accepted: 01/08/2023] [Indexed: 01/21/2023]
Abstract
Advanced pancreatic ductal adenocarcinoma (PDAC) is commonly treated with a chemotherapy combination of mFOLFIRINOX or gemcitabine. However, predictive and prognostic factors for choosing a more appropriate treatment strategy are still lacking. This study aimed to evaluate how chemotherapy changes immune system parameters and whether these changes influence survival outcomes. We sought to identify an easily accessible marker to help choose the appropriate treatment. Patients with PDAC who were suitable for systemic chemotherapy were eligible for the study. Peripheral blood samples were obtained at baseline and after two months of treatment. Lymphocyte subsets were measured using flow cytometry. Correlation with clinical features and survival analyses were performed. In total, 124 patients were enrolled in this study. Seventy patients were treated with mFOLFIRINOX and 50 with gemcitabine monotherapy. Four patients could not be treated because of rapid deterioration. During overall survival analysis (OS), significant factors included age, Eastern Cooperative Oncology Group (ECOG) performance status, differentiation grade G3, carcinoma antigen (CA) 19-9 more than 100 kU/L, absolute white blood cell count, CD3 + CD8+, and CD8 + CD57-T lymphocytes. Natural killer CD3-CD56 + CD16 + and CD3-CD56 + CD16- and T regulatory CD4 + FOXP3 + and CD3 + CD56 + cells differed during treatment, but these differences did not influence the survival results. At baseline, CD8 + CD57- T lymphocyte count demonstrated a clear independent impact on progression-free survival and OS. Gemcitabine showed better survival in patients with extremely low baseline CD8 + CD57- levels. Therefore, circulating CD3 + CD8 + and CD8 + CD57- cells measured before treatment in PDAC may be considered prognostic and predictive biomarkers.
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Affiliation(s)
- Skaiste Tulyte
- Clinic of Internal Diseases, Family Medicine and Oncology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
| | - Dainius Characiejus
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Reda Matuzeviciene
- Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Ausra Janiulioniene
- Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Mantas Radzevicius
- Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | | | - Tadas Zvirblis
- Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Audrius Sileikis
- Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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25
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Abstract
Pancreatic ductal adenocarcinomas are distinguished by their robust desmoplasia, or fibroinflammatory response. Dominated by non-malignant cells, the mutated epithelium must therefore combat, cooperate with or co-opt the surrounding cells and signalling processes in its microenvironment. It is proposed that an invasive pancreatic ductal adenocarcinoma represents the coordinated evolution of malignant and non-malignant cells and mechanisms that subvert and repurpose normal tissue composition, architecture and physiology to foster tumorigenesis. The complex kinetics and stepwise development of pancreatic cancer suggests that it is governed by a discrete set of organizing rules and principles, and repeated attempts to target specific components within the microenvironment reveal self-regulating mechanisms of resistance. The histopathological and genetic progression models of the transforming ductal epithelium must therefore be considered together with a programme of stromal progression to create a comprehensive picture of pancreatic cancer evolution. Understanding the underlying organizational logic of the tumour to anticipate and pre-empt the almost inevitable compensatory mechanisms will be essential to eradicate the disease.
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Affiliation(s)
- Sunil R Hingorani
- Division of Hematology and Oncology, Department of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, NE, USA.
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26
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Panahi M, Rezagholizadeh F, Mollazadehghomi S, Farhangnia P, Niya MHK, Ajdarkosh H, Tameshkel FS, Heshmati SM. The association between CD3+ and CD8+tumor-infiltrating lymphocytes (TILs) and prognosis in patients with pancreatic adenocarcinoma. Cancer Treat Res Commun 2023; 35:100699. [PMID: 36996584 DOI: 10.1016/j.ctarc.2023.100699] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023]
Abstract
BACKGROUND Pancreatic adenocarcinoma (PDAC), with more than 250,000 deaths each year, is the eighth leading cause of death worldwide, with a five-year survival of less than 5% and a median recurrence time between 5 and 23 months. The association between PDAC and CD3+/CD8+ tumor-infiltrating lymphocytes (TILs) and the extent of tumor spread and clinical outcomes has been recently shown. This study aimed to determine and compare the density of TILs and their association with disease prognosis in patients with PDAC. MATERIALS AND METHODS In this study, we collected PDAC tissues and corresponding adjacent normal tissues from 64 patients with TIL-positive PDAC. The immunohistochemistry method was used for the detection of the expression levels of CD3+ and CD8+ TILs in PDAC tissues. Also, the completed follow-up history was evaluated for at least five years. RESULTS The frequency of intratumoral and peritumoral TILs was 20 (31.2%) and 44 (68.8%), respectively. The mean density of CD3+ TILs and CD8+ TILs was 67.73%±20.17% and 69.45%±17.82%, respectively. The density of CD3+ TILs and CD8+ TILs was not associated with overall survival nor metastasis-free survival of the patients and tumor grade. However, the density of TILs was significantly lower in those patients who experienced tumor recurrence than those without this recurrence. CONCLUSION TILs density was high in patients with PDAC. The density of both CD3+ and CD8+ TILs was significantly lower in patients who experienced tumor recurrence. Thus, this study suggests that tracking and determining the density of CD3+ and CD8+ TILs might be effective in predicting PDAC recurrence.
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27
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Zhou L, Yang Y, Ma J, Liu M, Liu R, Ma X, Qiao C. Comprehensive analysis of alternative splicing signatures in pancreatic head cancer. IET Syst Biol 2022; 17:14-26. [PMID: 36479597 PMCID: PMC9931058 DOI: 10.1049/syb2.12056] [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: 03/14/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
The correlation between dysregulation of splicing and cancers has been increasingly recognised and confirmed. The identification of valuable alternative splicing (AS) in pancreatic head cancer (PHC) has a great significance. AS profiles in PHC were generated using the data from The Cancer Genome Atlas and TCGASpliceSeq. Then, the NMF clustering method was performed to identify overall survival-associated AS (OS-AS) subtypes in PHC patients. Subsequently, we used least absolute shrinkage and selection operator Cox regression analysis to construct an AS-related risk model. The splicing regulatory network was uncovered by Cytoscape 3.7. A total of 1694 OS-AS events were obtained. The PHC patients were divided into clusters 1 and 2. Cluster 1 had poorer prognosis and lower infiltration of immune cells. Subsequently, a prognostic signature was established that showed good performance in predicting OS and progression-free survival. The risk score of this signature was associated with the unique tumour immunity. Moreover, a nomogram incorporating the risk score and clinicopathological parameters was established. Finally, a splicing factor-AS regulatory network was developed. A comprehensive analysis of the AS events in PHC associated with prognosis and tumour immunity may help provide reliable information to guide individual treatment strategies.
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Affiliation(s)
- Lingshan Zhou
- Department of Geriatrics Ward 2the First Hospital of Lanzhou UniversityLanzhouChina
| | - Yuan Yang
- The First Clinical Medical CollegeLanzhou UniversityLanzhouChina,Department of Gastroenterologythe First Hospital of Lanzhou UniversityLanzhouChina,Gansu Key Laboratory of GastroenterologyLanzhou UniversityLanzhouChina
| | - Jian Ma
- Department of General Surgerythe First Hospital of Lanzhou UniversityLanzhouChina
| | - Min Liu
- Department of Gastroenterologythe First Hospital of Lanzhou UniversityLanzhouChina,Gansu Key Laboratory of GastroenterologyLanzhou UniversityLanzhouChina
| | - Rong Liu
- Department of Geriatrics Ward 2the First Hospital of Lanzhou UniversityLanzhouChina
| | - Xiaopeng Ma
- The First Clinical Medical CollegeLanzhou UniversityLanzhouChina,Department of General Surgerythe First Hospital of Lanzhou UniversityLanzhouChina
| | - Chengdong Qiao
- Department of Geriatrics Ward 2the First Hospital of Lanzhou UniversityLanzhouChina
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28
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Hughes R, Snook AE, Mueller AC. The poorly immunogenic tumor microenvironment of pancreatic cancer: the impact of radiation therapy, and strategies targeting resistance. Immunotherapy 2022; 14:1393-1405. [PMID: 36468417 DOI: 10.2217/imt-2022-0046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is one of the most lethal cancers, due to its uniquely aggressive behavior and resistance to therapy. The tumor microenvironment of pancreatic cancer is immunosuppressive, and attempts at utilizing immunotherapies have been unsuccessful. Radiation therapy (RT) results in immune activation and antigen presentation in other cancers, but in pancreatic cancer has had limited success in stimulating immune responses. RT activates common pathways of fibrosis and chronic inflammation seen in pancreatic cancer, resulting in immune suppression. Here we describe the pancreatic tumor microenvironment with regard to fibrosis, myeloid and lymphoid cells, and the impact of RT. We also describe strategies of targeting these pathways that have promise to improve outcomes by harnessing the cytotoxic and immune-activating aspects of RT.
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Affiliation(s)
- Robert Hughes
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Adam E Snook
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.,Department of Microbiology & Immunology, Thomas Jefferson University, Philadelphia, PA, USA; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Adam C Mueller
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
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29
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Heiduk M, Plesca I, Glück J, Müller L, Digomann D, Reiche C, von Renesse J, Decker R, Kahlert C, Sommer U, Aust DE, Schmitz M, Weitz J, Seifert L, Seifert AM. Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer. JCI Insight 2022; 7:152761. [PMID: 36509285 DOI: 10.1172/jci.insight.152761] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/12/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. At diagnosis, only 20% of patients with PDAC are eligible for primary resection. Neoadjuvant chemotherapy can enable surgical resection in 30%-40% of patients with locally advanced and borderline resectable PDAC. The effects of neoadjuvant chemotherapy on the cytokine production of tumor-infiltrating T cells are unknown in PDAC.METHODSWe performed multiplex immunofluorescence to investigate T cell infiltration in 91 patients with PDAC. Using flow cytometry, we analyzed tumor and matched blood samples from 71 patients with PDAC and determined the frequencies of T cell subsets and their cytokine profiles. Both cohorts included patients who underwent primary resection and patients who received neoadjuvant chemotherapy followed by surgical resection.RESULTSIn human PDAC, T cells were particularly enriched within the tumor stroma. Neoadjuvant chemotherapy markedly enhanced T cell density within the ductal area of the tumor. Whereas infiltration of cytotoxic CD8+ T cells was unaffected by neoadjuvant chemotherapy, the frequency of conventional CD4+ T cells was increased, and the proportion of Tregs was reduced in the pancreatic tumor microenvironment after neoadjuvant treatment. Moreover, neoadjuvant chemotherapy increased the production of proinflammatory cytokines by tumor-infiltrating T cells, with enhanced TNF-α and IL-2 and reduced IL-4 and IL-10 expression.CONCLUSIONNeoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile. Combinational treatment strategies incorporating immunotherapy in neoadjuvant regimens may unleash more effective antitumor responses and improve prognosis of pancreatic cancer.FUNDINGThis work was supported by the Jung Foundation for Science and Research, the Monika Kutzner Foundation, the German Research Foundation (SE2980/5-1), the German Cancer Consortium, and the Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden.
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Affiliation(s)
- Max Heiduk
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Ioana Plesca
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Jessica Glück
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Luise Müller
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - David Digomann
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Charlotte Reiche
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Janusz von Renesse
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Rahel Decker
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Christoph Kahlert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
| | - Ulrich Sommer
- Institute of Pathology, Faculty of Medicine Carl Gustav Carus, and
| | - Daniela E Aust
- Institute of Pathology, Faculty of Medicine Carl Gustav Carus, and.,National Center for Tumor Diseases, Biobank Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Marc Schmitz
- National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
| | - Lena Seifert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
| | - Adrian M Seifert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
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30
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Zhao T, Xiao D, Jin F, Sun X, Yu J, Wang H, Liu J, Cai W, Huang C, Wang X, Gao S, Liu Z, Yang S, Gao C, Hao J. ESE3-positive PSCs drive pancreatic cancer fibrosis, chemoresistance and poor prognosis via tumour-stromal IL-1β/NF-κB/ESE3 signalling axis. Br J Cancer 2022; 127:1461-1472. [PMID: 35986089 PMCID: PMC9553871 DOI: 10.1038/s41416-022-01927-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 07/08/2022] [Accepted: 07/15/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Desmoplastic stroma, a feature of pancreatic ductal adenocarcinoma (PDAC), contains abundant activated pancreatic stellate cells (PSCs). How PSCs promote PDAC progression remains incompletely understood. METHODS Effect of epithelium-specific E-twenty six factor 3 (ESE3)-positive PSCs on PDAC fibrosis and chemoresistance was examined by western blot, RT-PCR, immunofluorescence, flow cytometry assay, chromatin immunoprecipitation, luciferase assay, immunohistochemistry and subcutaneous pancreatic cancer mouse model. RESULTS ESE3 expression increased in PSCs in PDAC tissues compared with those in normal PSCs. Clinical data showed that ESE3 upregulation in PSCs was positively correlated with tumour size, pTNM stage, CA19-9, carcinoembryonic antigen and serum CA242 level. ESE3 overexpression in PSCs was an independent negative prognostic factor for disease-free survival and overall survival amongst patients with PDAC. Mechanistically, the conditional medium from the loss and gain of ESE3-expressing PSCs influenced PDAC chemoresistance and tumour growth. ESE3 directly induced the transcription of α-SMA, collagen-I and IL-1β by binding to ESE3-binding sites on their promoters to activate PSCs. IL-1β upregulated ESE3 in PSCs through NF-κB activation, and ESE3 was required for PSC activation by tumour cell-derived IL-1β. CONCLUSION Inhibiting the IL-1β/ESE3 (PSCs)/IL-1β-positive feedback loop is a promising therapeutic strategy to reduce tumour fibrosis and increase chemotherapeutic efficacy in PDAC.
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Affiliation(s)
- Tiansuo Zhao
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Di Xiao
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Fanjie Jin
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Xugang Sun
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Jie Yu
- grid.452461.00000 0004 1762 8478Hepatopancreatobiliary Surgery Department, First Hospital of Shanxi Medical University, Taiyuan, PR China
| | - Hongwei Wang
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Jing Liu
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Wenrun Cai
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Chongbiao Huang
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Xiuchao Wang
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Song Gao
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Zhe Liu
- grid.265021.20000 0000 9792 1228Department of Immunology, Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, PR China
| | - Shengyu Yang
- grid.240473.60000 0004 0543 9901Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA USA
| | - Chuntao Gao
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Jihui Hao
- grid.411918.40000 0004 1798 6427Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
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Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression. Cancers (Basel) 2022; 14:cancers14174265. [PMID: 36077801 PMCID: PMC9454580 DOI: 10.3390/cancers14174265] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/01/2022] [Accepted: 08/26/2022] [Indexed: 12/24/2022] Open
Abstract
Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.
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A Paradoxical Role for Regulatory T Cells in the Tumor Microenvironment of Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14163862. [PMID: 36010856 PMCID: PMC9405872 DOI: 10.3390/cancers14163862] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 07/18/2022] [Accepted: 08/05/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Pancreatic cancer is one of the most lethal cancer types and its high refractoriness to therapies, including immunotherapy, has often been associated with the predominantly immune suppressive tumor microenvironment that characterizes pancreatic tumors. Regulatory T cells (Tregs) are generally considered as drivers of immune suppression in cancers. However, an increasing number of reports suggest a paradoxical association between tumor infiltration by Tregs and improved patient prognosis, in particular in gastrointestinal cancers. Here we show that Treg infiltration in pancreatic ductal adenocarcinomas (PDAC) is associated with better overall survival of patients. Abstract Pancreatic ductal adenocarcinoma (PDAC) is considered to be a poorly immunogenic cancer type that combines a low mutation burden with a strong immunosuppressive tumor microenvironment. Regulatory T cells (Tregs) are major drivers of immune suppression but their prognostic role, particularly in gastrointestinal malignancies, remains controversial. Lymphocytic infiltration in 122 PDAC samples was assessed by multispectral immunofluorescence with anti-Keratin, -CD3, -CD8, -FOXP3 and -CD163 antibodies. Differential infiltration by Tregs was analyzed in the context of transcriptomic profiles that were available for 65 tumors. High infiltration of CD3+CD8− (mainly CD4+) T cells and, especially, of the subset expressing FOXP3 (Tregs) was associated with improved patient survival, whilst cytotoxic CD3+CD8+ T cell infiltration did not have an impact on overall survival. Transcriptomic analysis revealed three signatures in PDAC tumors comprising of epithelial-mesenchymal transition (EMT)/stromal, metabolic, and secretory/pancreatic signature. However, none of these signatures explained differences in Treg infiltration. We show that Tregs associate with improved overall survival in PDAC patients. This effect was independent of cytotoxic T cell infiltration and the transcriptomic profiles of their respective tumors. These findings provide a new layer of complexity in the study of PDAC tumor microenvironment that must be considered when developing immunotherapeutic interventions for this disease.
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Yan Y, Huang L, Liu Y, Yi M, Chu Q, Jiao D, Wu K. Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity. J Hematol Oncol 2022; 15:104. [PMID: 35948909 PMCID: PMC9364625 DOI: 10.1186/s13045-022-01322-3] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 07/26/2022] [Indexed: 11/17/2022] Open
Abstract
Characterized by the expression of the critical transcription factor forkhead box protein P3, regulatory T (Treg) cells are an essential part of the immune system, with a dual effect on the pathogenesis of autoimmune diseases and cancer. Targeting Tregs to reestablish the proinflammatory and immunogenic tumor microenvironment (TME) is an increasingly attractive strategy for cancer treatment and has been emphasized in recent years. However, attempts have been significantly hindered by the subsequent autoimmunity after Treg ablation owing to systemic loss of their suppressive capacity. Cellular metabolic reprogramming is acknowledged as a hallmark of cancer, and emerging evidence suggests that elucidating the underlying mechanisms of how intratumoral Tregs acquire metabolic fitness and superior immunosuppression in the TME may contribute to clinical benefits. In this review, we discuss the common and distinct metabolic profiles of Tregs in peripheral tissues and the TME, as well as the differences between Tregs and other conventional T cells in their metabolic preferences. By focusing on the critical roles of different metabolic programs, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, fatty acid synthesis, and amino acid metabolism, as well as their essential regulators in modulating Treg proliferation, migration, and function, we hope to provide new insights into Treg cell-targeted antitumor immunotherapies.
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Affiliation(s)
- Yuheng Yan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Lan Huang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yiming Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dechao Jiao
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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Tian X, Zheng J, Mou W, Lu G, Chen S, Du J, Zheng Y, Chen S, Shen B, Li J, Wang N. Development and validation of a hypoxia-stemness-based prognostic signature in pancreatic adenocarcinoma. Front Pharmacol 2022; 13:939542. [PMID: 35935823 PMCID: PMC9350896 DOI: 10.3389/fphar.2022.939542] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/30/2022] [Indexed: 12/14/2022] Open
Abstract
Background: Pancreatic adenocarcinoma (PAAD) is one of the most aggressive and fatal gastrointestinal malignancies with high morbidity and mortality worldwide. Accumulating evidence has revealed the clinical significance of the interaction between the hypoxic microenvironment and cancer stemness in pancreatic cancer progression and therapies. This study aims to identify a hypoxia-stemness index-related gene signature for risk stratification and prognosis prediction in PAAD.Methods: The mRNA expression-based stemness index (mRNAsi) data of PAAD samples from The Cancer Genome Atlas (TCGA) database were calculated based on the one-class logistic regression (OCLR) machine learning algorithm. Univariate Cox regression and LASSO regression analyses were then performed to establish a hypoxia-mRNAsi-related gene signature, and its prognostic performance was verified in both the TCGA-PAAD and GSE62452 corhorts by Kaplan-Meier and receiver operating characteristic (ROC) analyses. Additionally, we further validated the expression levels of signature genes using the TCGA, GTEx and HPA databases as well as qPCR experiments. Moreover, we constructed a prognostic nomogram incorporating the eight-gene signature and traditional clinical factors and analyzed the correlations of the risk score with immune infiltrates and immune checkpoint genes.Results: The mRNAsi values of PAAD samples were significantly higher than those of normal samples (p < 0.001), and PAAD patients with high mRNAsi values exhibited worse overall survival (OS). A novel prognostic risk model was successfully constructed based on the eight-gene signature comprising JMJD6, NDST1, ENO3, LDHA, TES, ANKZF1, CITED, and SIAH2, which could accurately predict the 1-, 3-, and 5-year OS of PAAD patients in both the training and external validation datasets. Additionally, the eight-gene signature could distinguish PAAD samples from normal samples and stratify PAAD patients into low- and high-risk groups with distinct OS. The risk score was closely correlated with immune cell infiltration patterns and immune checkpoint molecules. Moreover, calibration analysis showed the excellent predictive ability of the nomogram incorporating the eight-gene signature and traditional clinical factors.Conclusion: We developed a hypoxia-stemness-related prognostic signature that reliably predicts the OS of PAAD. Our findings may aid in the risk stratification and individual treatment of PAAD patients.
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Affiliation(s)
- Xiong Tian
- Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Jing Zheng
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Wanlan Mou
- Department of Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Guoguang Lu
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shuaishuai Chen
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Juping Du
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yufen Zheng
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shiyong Chen
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Bo Shen
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Jun Li
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- *Correspondence: Jun Li, ; Na Wang,
| | - Na Wang
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- *Correspondence: Jun Li, ; Na Wang,
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Kurz E, Hirsch CA, Dalton T, Shadaloey SA, Khodadadi-Jamayran A, Miller G, Pareek S, Rajaei H, Mohindroo C, Baydogan S, Ngo-Huang A, Parker N, Katz MHG, Petzel M, Vucic E, McAllister F, Schadler K, Winograd R, Bar-Sagi D. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell 2022; 40:720-737.e5. [PMID: 35660135 PMCID: PMC9280705 DOI: 10.1016/j.ccell.2022.05.006] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 03/30/2022] [Accepted: 05/10/2022] [Indexed: 01/13/2023]
Abstract
Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.
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Affiliation(s)
- Emma Kurz
- Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA
| | - Carolina Alcantara Hirsch
- Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA
| | - Tanner Dalton
- Department of Pathology, Columbia University Irving Medical Center, 630 W 168th St., New York, NY 10032, USA
| | - Sorin Alberto Shadaloey
- Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA
| | - Alireza Khodadadi-Jamayran
- Applied Bioinformatics Laboratory, NYU Grossman School of Medicine, 227 East 30(th) St., New York, NY 10016, USA
| | - George Miller
- Department of Surgery, Trinity Health New England, 56 Franklin St., Waterbury, CT 06706, USA
| | - Sumedha Pareek
- Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Hajar Rajaei
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Chirayu Mohindroo
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Seyda Baydogan
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - An Ngo-Huang
- Department of Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Nathan Parker
- Department of Health Outcomes and Behavior, Moffit Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Matthew H G Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Maria Petzel
- Department of Clinical Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Emily Vucic
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; Gastrointestinal Medical Oncology and Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston TX, 77030, USA
| | - Keri Schadler
- Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Rafael Winograd
- Permultter Cancer Center, NYU Langone Health, 160 East 34(th) St., New York, NY 10016, USA
| | - Dafna Bar-Sagi
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA.
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36
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Chamma H, Vila IK, Taffoni C, Turtoi A, Laguette N. Activation of STING in the pancreatic tumor microenvironment: A novel therapeutic opportunity. Cancer Lett 2022; 538:215694. [PMID: 35489447 DOI: 10.1016/j.canlet.2022.215694] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/21/2022] [Accepted: 04/15/2022] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a cancer of poor prognosis that presents with a dense desmoplastic stroma that contributes to therapeutic failure. PDAC patients are mostly unresponsive to immunotherapy. However, hopes to elicit response to immunotherapy have emerged with novel strategies targeting the Stimulator of Interferon Genes (STING) protein, which is a major regulator of tumor-associated inflammation. Combination of STING agonists with conventional immunotherapy approaches has proven to potentiate therapeutic benefits in several cancers. However, recent data underscore that the output of STING activation varies depending on the cellular and tissue context. This suggests that tumor heterogeneity, and in particular the heterogeneity of the tumor microenvironment (TME), is a key factor determining whether STING activation would bear benefits for patients. In this review, we discuss the potential benefits of STING activation in PDAC. To this aim, we describe the major components of the PDAC TME, and the expected consequences of STING activation.
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Affiliation(s)
- Hanane Chamma
- Institut de Génétique Humaine, CNRS, Université de Montpellier, Molecular Basis of Inflammation Laboratory, Montpellier, France
| | - Isabelle K Vila
- Institut de Génétique Humaine, CNRS, Université de Montpellier, Molecular Basis of Inflammation Laboratory, Montpellier, France
| | - Clara Taffoni
- Institut de Génétique Humaine, CNRS, Université de Montpellier, Molecular Basis of Inflammation Laboratory, Montpellier, France
| | - Andrei Turtoi
- Tumor Microenvironment Laboratory, Institut de Recherche en Cancérologie de Montpellier, Université de Montpellier, INSERM U1194, 34000, Montpellier, France.
| | - Nadine Laguette
- Institut de Génétique Humaine, CNRS, Université de Montpellier, Molecular Basis of Inflammation Laboratory, Montpellier, France.
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Aristin Revilla S, Kranenburg O, Coffer PJ. Colorectal Cancer-Infiltrating Regulatory T Cells: Functional Heterogeneity, Metabolic Adaptation, and Therapeutic Targeting. Front Immunol 2022; 13:903564. [PMID: 35874729 PMCID: PMC9304750 DOI: 10.3389/fimmu.2022.903564] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/06/2022] [Indexed: 11/18/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low-dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches. Here, we review our understanding of the role of Treg cells in CRC, the possible mechanisms that support their homeostasis in the tumor microenvironment, and current approaches for manipulating Treg cells function in cancer.
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Affiliation(s)
- Sonia Aristin Revilla
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Onno Kranenburg
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Paul J. Coffer
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
- *Correspondence: Paul J. Coffer,
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Agostini A, Orlacchio A, Carbone C, Guerriero I. Understanding Tricky Cellular and Molecular Interactions in Pancreatic Tumor Microenvironment: New Food for Thought. Front Immunol 2022; 13:876291. [PMID: 35711414 PMCID: PMC9193393 DOI: 10.3389/fimmu.2022.876291] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/29/2022] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents 90% of all pancreatic cancer cases and shows a high mortality rate among all solid tumors. PDAC is often associated with poor prognosis, due to the late diagnosis that leads to metastasis development, and limited efficacy of available treatments. The tumor microenvironment (TME) represents a reliable source of novel targets for therapy, and even if many of the biological interactions among stromal, immune, and cancer cells that populate the TME have been studied, much more needs to be clarified. The great limitation in the efficacy of current standard chemoterapy is due to both the dense fibrotic inaccessible TME barrier surrounding cancer cells and the immunological evolution from a tumor-suppressor to an immunosuppressive environment. Nevertheless, combinatorial therapies may prove more effective at overcoming resistance mechanisms and achieving tumor cell killing. To achieve this result, a deeper understanding of the pathological mechanisms driving tumor progression and immune escape is required in order to design rationale-based therapeutic strategies. This review aims to summarize the present knowledge about cellular interactions in the TME, with much attention on immunosuppressive functioning and a specific focus on extracellular matrix (ECM) contribution.
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Affiliation(s)
- Antonio Agostini
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Medical Oncology, Department of Translational Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Arturo Orlacchio
- NYU Grossman School of Medicine, NYU Langone Health, New York, NY, United States
| | - Carmine Carbone
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Ilaria Guerriero
- Biogem, Biology and Molecular Genetics Institute, Ariano Irpino, Italy
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Elkoshi Z. On the Prognostic Power of Tumor-Infiltrating Lymphocytes – A Critical Commentary. Front Immunol 2022; 13:892543. [PMID: 35634289 PMCID: PMC9133417 DOI: 10.3389/fimmu.2022.892543] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor-infiltrating lymphocytes are extensively used as prognostic biomarkers in cancer. Regulatory T cells (Tregs) or CD8+ T cells frequencies in tumor site, or their ratio, are the most common markers used to assess prognosis. This work offers a possible explanation for the opposite correlations between intra-tumoral Tregs and survival, associated with different types of cancer. The complexity involved with the selection of a preferred marker, including the effect of variability, is presented and discussed. The lymphocytes frequency ratio is proposed as the marker of choice in most types of cancer. The ratio correlates directly with survival, irrespective of cancer type and is also less variable than the frequencies of each of the two lymphocytes, if these frequencies correlate with each other in the tumor microenvironment. However, if the frequency of one of the two lymphocytes is highly variable, abandoning the ratio in favor of the lymphocyte with less variable frequency will improve correlation with survival, especially when the intra-tumoral frequencies of the two species are inversely correlated. It is plausible, that the best prognostic marker selected this way, will be also be the best predictor of checkpoint inhibitor therapy success.
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Gartrell RD, Enzler T, Kim PS, Fullerton BT, Fazlollahi L, Chen AX, Minns HE, Perni S, Weisberg SP, Rizk EM, Wang S, Oh EJ, Guo XV, Chiuzan C, Manji GA, Bates SE, Chabot J, Schrope B, Kluger M, Emond J, Rabadán R, Farber D, Remotti HE, Horowitz DP, Saenger YM. Neoadjuvant chemoradiation alters the immune microenvironment in pancreatic ductal adenocarcinoma. Oncoimmunology 2022; 11:2066767. [PMID: 35558160 PMCID: PMC9090285 DOI: 10.1080/2162402x.2022.2066767] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 01/21/2023] Open
Abstract
Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3+ T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3+CD8+ cytotoxic T cells (CTLs, p = .0079), CD3+CD4+FOXP3- T helper cells (Th, p = .0010), and CD3+CD4+FOXP3+ regulatory T cells (Tregs, p = .0089) with no difference in CD68+ macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor.
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Affiliation(s)
- Robyn D. Gartrell
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Thomas Enzler
- Rogel Cancer Center, University of Michigan Medicine, Ann Arbor, MI, USA
| | - Pan S. Kim
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Benjamin T. Fullerton
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Ladan Fazlollahi
- Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA
| | - Andrew X. Chen
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Hanna E. Minns
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Subha Perni
- Harvard Radiation Oncology Program, Massachusetts General Hospital and Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA, USA
| | - Stuart P. Weisberg
- Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA
| | - Emanuelle M. Rizk
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Samuel Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Eun Jeong Oh
- Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Xinzheng V. Guo
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Codruta Chiuzan
- Department of Biostatistics, Columbia University Irving Medical Center, New York, NY, USA
| | - Gulam A. Manji
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Susan E. Bates
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - John Chabot
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Beth Schrope
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael Kluger
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Jean Emond
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Raul Rabadán
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Donna Farber
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA
| | - Helen E. Remotti
- Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA
| | - David P. Horowitz
- Department of Radiation Oncology, Columbia University Irving Medical Center, New York, NY, USA
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A Novel Immune-Related Prognostic Signature Predicting Survival in Patients with Pancreatic Adenocarcinoma. JOURNAL OF ONCOLOGY 2022; 2022:8909631. [PMID: 35342420 PMCID: PMC8956421 DOI: 10.1155/2022/8909631] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 11/03/2021] [Accepted: 02/16/2022] [Indexed: 12/13/2022]
Abstract
Pancreatic adenocarcinoma (PAAD) carries the lowest survival rate of all major organ cancers, which is of dismal prognosis and high mortality rate. Thus, the present study attempted to identify a few novel prognostic biomarkers and establish an immune-related prognostic signature which could predict the prognosis of PAAD. Four prognostic immune-related genes (IRGs) including S100A6, S100A10, S100A16, and SDC1 were screened by differentially expressed gene (DEG) identification and weighted gene coexpression network analysis (WGCNA). Subsequent analysis proved the high expression of these IRGs in PAAD tissues, suggested by TCGA-PAAD data, merged microarray-acquired dataset (MMD), GEPIA, and Oncomine webtool. By using MMD and TCGA-PAAD data, S100A6 (MMD: AUC = 0.897; TCGA: AUC = 0.843), S100A10 (MMD: AUC = 0.880; TCGA: AUC = 0.780), S100A16 (MMD: AUC = 0.878; TCGA: AUC = 0.838), and SDC1 (MMD: AUC = 0.885; TCGA: AUC = 0.812) exhibited excellent diagnostic efficiency for PAAD. By conducting connectivity map (CMap) analysis, we concluded that three molecule drugs (sulpiride, famotidine, and nalidixic acid) might have worked in the treatment of PAAD. Then, an immune-related prognostic index was constructed, which was validated as an independent prognostic factor for PAAD patients (P=0.004). We further constructed a nomogram by using this immune-related signature and age, the prognostic value of which was validated by using concordance index (C-index = 0.780) and area under curve (AUC = 0.909). Moreover, the immune-related prognostic signature was associated with response to anti-PD-1/L1 immunotherapy. To sum up, four IRGs were screened out and verified to be novel immune-related prognostic biomarkers in PAAD. Besides, sulpiride, famotidine, and nalidixic acid might be potential choices in the treatment of PAAD. An immune-related signature was established to show great potential for prognosis prediction for PAAD, independently, which might guide more effective immunotherapy strategies. A nomogram is further established by using this immune-related prognostic index, which might contribute to more effective prognosis prediction in PAAD patients.
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Hong MMY, Maleki Vareki S. Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy. Cancers (Basel) 2022; 14:1580. [PMID: 35326731 PMCID: PMC8946681 DOI: 10.3390/cancers14061580] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/14/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023] Open
Abstract
Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T-cells (Tregs) that can inhibit the activation of effector T-cells. Anti-CTLA-4 therapy can confer long-lasting clinical benefits in cancer patients as a single agent or in combination with other immunotherapy agents. However, patient response rates to anti-CTLA-4 are relatively low, and a high percentage of patients experience severe immune-related adverse events. Clinical use of anti-CTLA-4 has regained interest in recent years; however, the mechanism(s) of anti-CTLA-4 is not well understood. Although activating T-cells is regarded as the primary anti-tumor mechanism of anti-CTLA-4 therapies, mounting evidence in the literature suggests targeting intra-tumoral Tregs as the primary mechanism of action of these agents. Tregs in the tumor microenvironment can suppress the host anti-tumor immune responses through several cell contact-dependent and -independent mechanisms. Anti-CTLA-4 therapy can enhance the priming of T-cells by blockading CD80/86-CTLA-4 interactions or depleting Tregs through antibody-dependent cellular cytotoxicity and phagocytosis. This review will discuss proposed fundamental mechanisms of anti-CTLA-4 therapy, novel uses of anti-CTLA-4 in cancer treatment and approaches to improve the therapeutic efficacy of anti-CTLA-4.
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Affiliation(s)
- Megan M Y Hong
- Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON N6A 3K7, Canada;
| | - Saman Maleki Vareki
- Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON N6A 3K7, Canada;
- London Regional Cancer Program, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Oncology, University of Western Ontario, London, ON N6A 3K7, Canada
- Department of Medical Biophysics, University of Western Ontario, London, ON N6A 3K7, Canada
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43
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Muller M, Haghnejad V, Schaefer M, Gauchotte G, Caron B, Peyrin-Biroulet L, Bronowicki JP, Neuzillet C, Lopez A. The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges. Cancers (Basel) 2022; 14:cancers14040995. [PMID: 35205742 PMCID: PMC8870260 DOI: 10.3390/cancers14040995] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 02/04/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide with an overall survival rate, all stages combined, of still <10% at 5 years. The poor prognosis is attributed to challenges in early detection, a low opportunity for radical resection, limited response to chemotherapy, radiotherapy, and resistance to immune therapy. Moreover, pancreatic tumoral cells are surrounded by an abundant desmoplastic stroma, which is responsible for creating a mechanical barrier, preventing appropriate vascularization and leading to poor immune cell infiltration. Accumulated evidence suggests that PDAC is impaired with multiple “immune defects”, including a lack of high-quality effector cells (CD4, CD8 T cells, dendritic cells), barriers to effector cell infiltration due to that desmoplastic reaction, and a dominance of immune cells such as regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages, resulting in an immunosuppressive tumor microenvironment (TME). Although recent studies have brought new insights into PDAC immune TME, its understanding remains not fully elucidated. Further studies are required for a better understanding of human PDAC immune TME, which might help to develop potent new therapeutic strategies by correcting these immune defects with the hope to unlock the resistance to (immune) therapy. In this review, we describe the main effector immune cells and immunosuppressive actors involved in human PDAC TME, as well as their implications as potential biomarkers and therapeutic targets.
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Affiliation(s)
- Marie Muller
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- Correspondence:
| | - Vincent Haghnejad
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Marion Schaefer
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Guillaume Gauchotte
- Department of Pathology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France;
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Bénédicte Caron
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Jean-Pierre Bronowicki
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Cindy Neuzillet
- Medical Oncology Department, Curie Institute, Versailles Saint-Quentin University (UVQ), Paris Saclay University, 92064 Saint-Cloud, France;
| | - Anthony Lopez
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
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Huppert LA, Green MD, Kim L, Chow C, Leyfman Y, Daud AI, Lee JC. Tissue-specific Tregs in cancer metastasis: opportunities for precision immunotherapy. Cell Mol Immunol 2022; 19:33-45. [PMID: 34417572 PMCID: PMC8752797 DOI: 10.1038/s41423-021-00742-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/28/2021] [Indexed: 12/27/2022] Open
Abstract
Decades of advancements in immuno-oncology have enabled the development of current immunotherapies, which provide long-term treatment responses in certain metastatic cancer patients. However, cures remain infrequent, and most patients ultimately succumb to treatment-refractory metastatic disease. Recent insights suggest that tumors at certain organ sites exhibit distinctive response patterns to immunotherapy and can even reduce antitumor immunity within anatomically distant tumors, suggesting the activation of tissue-specific immune tolerogenic mechanisms in some cases of therapy resistance. Specialized immune cells known as regulatory T cells (Tregs) are present within all tissues in the body and coordinate the suppression of excessive immune activation to curb autoimmunity and maintain immune homeostasis. Despite the high volume of research on Tregs, the findings have failed to reconcile tissue-specific Treg functions in organs, such as tolerance, tissue repair, and regeneration, with their suppression of local and systemic tumor immunity in the context of immunotherapy resistance. To improve the understanding of how the tissue-specific functions of Tregs impact cancer immunotherapy, we review the specialized role of Tregs in clinically common and challenging organ sites of cancer metastasis, highlight research that describes Treg impacts on tissue-specific and systemic immune regulation in the context of immunotherapy, and summarize ongoing work reporting clinically feasible strategies that combine the specific targeting of Tregs with systemic cancer immunotherapy. Improved knowledge of Tregs in the framework of their tissue-specific biology and clinical sites of organ metastasis will enable more precise targeting of immunotherapy and have profound implications for treating patients with metastatic cancer.
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Affiliation(s)
- Laura A Huppert
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Michael D Green
- Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA
- Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - Luke Kim
- University of California, San Francisco School of Medicine, San Francisco, CA, USA
| | - Christine Chow
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Yan Leyfman
- Penn State College of Medicine, Hershey, PA, USA
| | - Adil I Daud
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - James C Lee
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
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45
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Zhao W, Dai S, Yue L, Xu F, Gu J, Dai X, Qian X. Emerging mechanisms progress of colorectal cancer liver metastasis. Front Endocrinol (Lausanne) 2022; 13:1081585. [PMID: 36568117 PMCID: PMC9772455 DOI: 10.3389/fendo.2022.1081585] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastasis. The hepatic portal venous system, responsible for collecting most intestinal blood, makes the liver the most common site of CRC metastasis. The formation of liver metastases from colorectal cancer is a long and complex process. It involves the maintenance of primary tumors, vasculature invasion, distant colonization, and metastasis formation. In this review, we serve on how the CRC cells acquire stemness, invade the vascular, and colonize the liver. In addition, we highlight how the resident cells of the liver and immune cells interact with CRC cells. We also discuss the current immunotherapy approaches and challenges we face, and finally, we look forward to finding new therapeutic targets based on novel sequencing technologies.
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Cortesi M, Zanoni M, Pirini F, Tumedei MM, Ravaioli S, Rapposelli IG, Frassineti GL, Bravaccini S. Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight. Int J Mol Sci 2021; 23:ijms23010254. [PMID: 35008679 PMCID: PMC8745092 DOI: 10.3390/ijms23010254] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/21/2021] [Accepted: 12/24/2021] [Indexed: 01/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the most dismal prognoses of all cancers due to its late manifestation and resistance to current therapies. Accumulating evidence has suggested that the malignant behavior of this cancer is mainly influenced by the associated strongly immunosuppressive, desmoplastic microenvironment and by the relatively low mutational burden. PDAC develops and progresses through a multi-step process. Early in tumorigenesis, cancer cells must evade the effects of cellular senescence, which slows proliferation and promotes the immune-mediated elimination of pre-malignant cells. The role of senescence as a tumor suppressor has been well-established; however, recent evidence has revealed novel pro-tumorigenic paracrine functions of senescent cells towards their microenvironment. Understanding the interactions between tumors and their microenvironment is a growing research field, with evidence having been provided that non-tumoral cells composing the tumor microenvironment (TME) influence tumor proliferation, metabolism, cell death, and therapeutic resistance. Simultaneously, cancer cells shape a tumor-supportive and immunosuppressive environment, influencing both non-tumoral neighboring and distant cells. The overall intention of this review is to provide an overview of the interplay that occurs between senescent and non-senescent cell types and to describe how such interplay may have an impact on PDAC progression. Specifically, the effects and the molecular changes occurring in non-cancerous cells during senescence, and how these may contribute to a tumor-permissive microenvironment, will be discussed. Finally, senescence targeting strategies will be briefly introduced, highlighting their potential in the treatment of PDAC.
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Affiliation(s)
- Michela Cortesi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
- Correspondence:
| | - Michele Zanoni
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
| | - Francesca Pirini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
| | - Maria Maddalena Tumedei
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
| | - Sara Ravaioli
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
| | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (G.L.F.)
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (G.L.F.)
| | - Sara Bravaccini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
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47
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The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis. Cancers (Basel) 2021; 13:cancers13246206. [PMID: 34944826 PMCID: PMC8699466 DOI: 10.3390/cancers13246206] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is the third most common cancer worldwide. Metastasis to secondary organs, such as the liver and lungs, is a key driver of CRC-related mortality. The tumor microenvironment, which consists of the primary cancer cells, as well as associated support and immune cells, significantly affects the behavior of CRC cells at the primary tumor site, as well as in metastatic lesions. In this paper, we review the role of the individual components of the tumor microenvironment on tumor progression, immune evasion, and metastasis, and we discuss the implications of these components on antitumor therapies. Abstract Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.
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Opitz FV, Haeberle L, Daum A, Esposito I. Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia. Cancers (Basel) 2021; 13:cancers13246188. [PMID: 34944807 PMCID: PMC8699458 DOI: 10.3390/cancers13246188] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive neoplasm with a poor survival rate. This is mainly due to late detection, which substantially limits therapy options. A better understanding of the early phases of pancreatic carcinogenesis is fundamental for improving patient prognosis in the future. In this article, we focused on the tumor microenvironment (TME), which provides the biological niche for the development of PDAC from its most common precursor lesions, PanIN (pancreatic intraepithelial neoplasias). Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.
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Lisnawati L, Billianti YD, Manatar AF. Association between Foxp3 Tumor Infiltrating Lymphocyte Expression and Response After Chemoradiation in Nasopharyngeal Carcinoma. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a carcinoma originating from the surface epithelium of the nasopharynx with the highest incidence in China and South East Asia. Currently, many researchers are developing tumor microenvironment which can be assessed by tumor-infiltrating lymphochyte, and its association with treatment response in several tumors, including NPC. Foxp3, known as a regulatory T cell (Treg) marker, plays a role in the immunoregulatory environment of tumor cells and can be used as a prognostic factor. The relationship between Foxp3 expression and treatment response is considered as one of the factors affecting the prognosis of NPC.
AIM: This study aims to determine the relationship between Foxp3 expression and treatment response in NPC.
MATERIALS AND METHODS: A cross-sectional study was done to analyze the association between Foxp3 and treatment response in NPC. This study included 60 samples who were diagnosed with non-keratinizing NPC at the Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/Cipto Mangunkusumo Hospital from January 2018 until December 2020. Immunohistochemistry was done to evaluate the expression of Foxp3. Foxp3 expression was evaluated in the intratumoral and peritumoral areas.
RESULTS: Among 60 patients, the number of males were more than females (66.7%, 33.3%, respectively) with a ratio of 2:1. There was statistically significant difference between intratumoral and total Foxp3 expression and treatment response (p < 0.05, p = 0.001, respectively); however, no significant differences found between peritumoral Foxp3 expression and treatment response (p = 0.114).
CONCLUSION: Foxp3 expression had a statistically significant relationship with response therapy after chemoradiation.
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Ota S, Miyashita M, Yamagishi Y, Ogasawara M. Baseline immunity predicts prognosis of pancreatic cancer patients treated with WT1 and/or MUC1 peptide-loaded dendritic cell vaccination and a standard chemotherapy. Hum Vaccin Immunother 2021; 17:5563-5572. [PMID: 34919493 PMCID: PMC8903979 DOI: 10.1080/21645515.2021.2003645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 10/15/2021] [Accepted: 11/04/2021] [Indexed: 12/15/2022] Open
Abstract
The prognosis of patients with advanced pancreatic cancer is poor despite the recent introduction of immune checkpoint inhibitors. Therefore, the development of new therapeutic approaches is urgently required. In the present phase I/II study, we have evaluated the safety, the efficacy and the prognostic factors of Wilms' tumor 1 (WT1) and/or mucin 1 (MUC1) peptide-loaded dendritic cell (DC) vaccination in combination with a chemotherapy employing gemcitabine plus nab-paclitaxel or a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) in patients with advanced or relapsed pancreatic ductal adenocarcinoma (PDAC). Forty-eight eligible patients were enrolled and received the vaccinations approximately every 2-4 weeks at least seven times. No severe adverse events related to the vaccinations were observed. Median progression free survival and overall survival were 8.1 months and 15.1 months, respectively. DC vaccinations augmented tumor specific immunity which might be related to clinical outcome. The multivariate analyses demonstrated that WT1 or MUC1-specific interferonɤ enzyme-linked immunospot number prior to DC vaccination was an independent prognostic factor related to overall survival. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and has clinical benefits for patients in advanced stage of PDAC. The precise evaluation of the baseline antitumor specific immunity is critical to predict clinical outcome.
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Affiliation(s)
- Shuichi Ota
- Department of Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Mamiko Miyashita
- Institute for Artificial Organ, Transplantation and Cell Therapy, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Yuka Yamagishi
- Cell Processing Center, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Masahiro Ogasawara
- Department of Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, Japan
- Institute for Artificial Organ, Transplantation and Cell Therapy, Sapporo Hokuyu Hospital, Sapporo, Japan
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