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Rahimi A, Baghernejadan Z, Hazrati A, Malekpour K, Samimi LN, Najafi A, Falak R, Khorramdelazad H. Combination therapy with immune checkpoint inhibitors in colorectal cancer: Challenges, resistance mechanisms, and the role of microbiota. Biomed Pharmacother 2025; 186:118014. [PMID: 40157004 DOI: 10.1016/j.biopha.2025.118014] [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: 01/08/2025] [Revised: 03/17/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025] Open
Abstract
Colorectal cancer (CRC) is still one of the leading causes of cancer deaths worldwide. Even though there has been progress in cancer immunotherapy, the results of applying immune checkpoint inhibitors (ICIs) have been unsatisfactory, especially in microsatellite stable (MSS) CRC. Single-agent ICIs that target programmed cell death-1 (PD-1)/ PD-L1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell Ig- and mucin-domain-containing molecule-3 (TIM-3), and lymphocyte activation gene (LAG)-3 have emerged as having specific benefits. However, many primary and secondary resistance mechanisms are available in the tumor microenvironment (TME) that prevent it from happening. Combination strategies, such as the use of anti-PD-1 and anti-CTLA-4, can be effective in overcoming these resistance pathways, but toxicities remain a significant concern. Moreover, ICIs have been integrated with various treatment modalities, including chemotherapy, radiotherapy, antibiotics, virotherapy, polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, and heat shock protein 90 (HSP90) inhibitors. The outcomes observed in both preclinical and clinical settings have been encouraging. Interestingly, manipulating gut microbiota via fecal microbiota transplantation (FMT) has been identified as a new strategy to increase the efficacy of immunotherapy in CRC patients. Therefore, integrating ICIs with other treatment approaches holds promise in enhancing the prognosis of CRC patients. This review focuses on the unmet need for new biomarkers to select patients for combination therapies and the ongoing work to overcome resistance and immune checkpoint blockade.
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Affiliation(s)
- Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Baghernejadan
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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Marongiu GL, Fink U, Schöpf F, Oder A, von Kries JP, Roderer D. Structural basis for immune cell binding of Fusobacterium nucleatum via the trimeric autotransporter adhesin CbpF. Proc Natl Acad Sci U S A 2025; 122:e2418155122. [PMID: 40198705 PMCID: PMC12012533 DOI: 10.1073/pnas.2418155122] [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: 09/06/2024] [Accepted: 03/05/2025] [Indexed: 04/10/2025] Open
Abstract
Fusobacterium nucleatum (Fn), a commensal in the human oral cavity, is overrepresented in the colon microbiota of colorectal cancer (CRC) patients and is linked to tumor chemoresistance, metastasis, and a poor therapeutic prognosis. Fn produces numerous adhesins that mediate tumor colonization and downregulation of the host's antitumor immune response. One of these, the trimeric autotransporter adhesin (TAA) CEACAM binding protein of Fusobacterium (CbpF), targets CEACAM1 on T-cells and has been associated with immune evasion of Fn-colonized tumors. Whereas the role of CEACAM1 in homophilic and heterophilic cell interactions and immune evasion is well described, the mechanistic details of its interaction with fusobacterial CbpF remain unknown due to the lack of a high-resolution structure of the adhesin-receptor complex. Here, we present two structures of CbpF alone and in complex with CEACAM1, obtained by cryogenic electron microscopy and single particle analysis. They reveal that CbpF forms a stable homotrimeric complex whose N-terminal part of the extracellular domain comprises a 64 Å long β roll domain with a unique lateral loop extension. CEACAM1 binds to this loop with high affinity via its N-terminal IgV-like domain with a nanomolar dissociation constant as determined by surface plasmon resonance. This study provides a comprehensive structural description of a fusobacterial TAA, illustrates a yet undescribed CEACAM1 binding mode, and paves the way for rational drug design targeting Fn in CRC.
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Affiliation(s)
- Gian Luca Marongiu
- Leibniz-Forschungsinstitut fur Molekulare Pharmakologie, Berlin13125, Germany
| | - Uwe Fink
- Leibniz-Forschungsinstitut fur Molekulare Pharmakologie, Berlin13125, Germany
| | - Felix Schöpf
- Leibniz-Forschungsinstitut fur Molekulare Pharmakologie, Berlin13125, Germany
| | - Andreas Oder
- Leibniz-Forschungsinstitut fur Molekulare Pharmakologie, Screening Unit, Berlin13125, Germany
| | - Jens Peter von Kries
- Leibniz-Forschungsinstitut fur Molekulare Pharmakologie, Screening Unit, Berlin13125, Germany
| | - Daniel Roderer
- Leibniz-Forschungsinstitut fur Molekulare Pharmakologie, Berlin13125, Germany
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Deng RZ, Zheng X, Lu ZL, Yuan M, Meng QC, Wu T, Tian Y. Effect of colorectal cancer stem cells on the development and metastasis of colorectal cancer. World J Gastrointest Oncol 2024; 16:4354-4368. [PMID: 39554751 PMCID: PMC11551631 DOI: 10.4251/wjgo.v16.i11.4354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/24/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role - immune checkpoints - and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Run-Zhi Deng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Xin Zheng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Zhong-Lei Lu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Ming Yuan
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Qi-Chang Meng
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Tao Wu
- Department of General Surgery, West China Hospital of Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Yu Tian
- Department of Thoracic Surgery, Yancheng No. 1 People’s Hospital, Affiliated Hospital of Nanjing University Medical School, The First People’s Hospital of Yancheng, Yancheng 224000, Jiangsu Province, China
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Zhang Y, Zhang C, Chen G, You H, Wang S, Wang X, Zhao P, Xu B, Gao Q, Yuan L. Subclone from CT26 resistant to anti-PD-1 therapy associated with increased expression of genes related to glucocorticoids. Transl Oncol 2024; 46:102031. [PMID: 38861853 PMCID: PMC11209639 DOI: 10.1016/j.tranon.2024.102031] [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: 03/08/2024] [Revised: 05/22/2024] [Accepted: 06/05/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Although the use of anti-PD-1 antibodies has fundamentally changed traditional cancer treatment, most patients are resistant to anti-PD-1 treatment. Glucocorticoids (GCs) play an important role in tumorigenesis and tumor progression, but the role of endogenous GCs in resistance to anti-PD-1 antibody therapy remains unclear. METHODS Single cell-derived cell lines (SCDCLs) were generated from a colorectal cancer cell line (CT26) using limiting dilution. We analyzed tumor tissues from anti-PD-1 antibody-treated and untreated mice inoculated with SCDCLs via transcriptome sequencing and flow cytometry to detect pathway activity and immune cell composition changes in the tumor microenvironment. RESULTS Five SCDCLs were inoculated into wild-type BALB/c mice (all tumorigenic). Single-cell clone (SCC)-2 exhibited the slowest growth rates both in vivo and in vitro compared to other single-cell clones, and better long-term survival than SCC1 and CT26. Flow cytometry showed that SCC2 tumor-bearing mice exhibited significantly higher infiltration of T cells within the tumor tissue, and higher expression of PD-1 on these T cells than the other groups in vivo. However, the SCC2 group showed no response to anti-PD-1 therapy. Transcriptome analysis revealed that the SCC2 group exhibited increased expression of genes related to GC (Hsd11b1, Sgk3, Tgfbr2, and Il7r) compared to SCC2-anti-PD-1 treated tumors. CONCLUSIONS GC pathway activation is related to resistance to anti-PD-1 therapy.
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Affiliation(s)
- Yangyang Zhang
- Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China
| | - Chaoji Zhang
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Guangyu Chen
- Department of immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China
| | - Hongqin You
- Department of immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China
| | - Sen Wang
- Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China
| | - Xiaoming Wang
- Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China
| | - Peng Zhao
- Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China
| | - Benling Xu
- Department of immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China.
| | - Quanli Gao
- Department of immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China.
| | - Long Yuan
- Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China.
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Ito M, Mimura K, Nakajima S, Okayama H, Saito K, Nakajima T, Kikuchi T, Onozawa H, Fujita S, Sakamoto W, Saito M, Momma T, Saze Z, Kono K. M2 tumor-associated macrophages resist to oxidative stress through heme oxygenase-1 in the colorectal cancer tumor microenvironment. Cancer Immunol Immunother 2023; 72:2233-2244. [PMID: 36869896 PMCID: PMC10992489 DOI: 10.1007/s00262-023-03406-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 02/11/2023] [Indexed: 03/05/2023]
Abstract
M2 tumor-associated macrophages (M2-TAMs) promote cancer cell proliferation and metastasis in the TME. Our study aimed to elucidate the mechanism of increased frequency of M2-TAMs infiltration in the colorectal cancer (CRC)-TME, focusing on the resistance to oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we evaluated the correlation between M2-TAM signature and mRNA expression of antioxidant related genes using public datasets, and the expression level of antioxidants in M2-TAMs by flow cytometry and the prevalence of M2-TAMs expressing antioxidants by immunofluorescence staining using surgically resected specimens of CRC (n = 34). Moreover, we generated M0 and M2 macrophages from peripheral blood monocytes and evaluated their resistance to oxidative stress using the in vitro viability assay. Analysis of GSE33113, GSE39582, and The Cancer Genome Atlas (TCGA) datasets indicated that mRNA expression of HMOX1 (heme oxygenase-1 (HO-1)) was significantly positively correlated with M2-TAM signature (r = 0.5283, r = 0.5826, r = 0.5833, respectively). The expression level of both Nrf2 and HO-1 significantly increased in M2-TAMs compared to M1- and M1/M2-TAMs in the tumor margin, and the number of Nrf2+ or HO-1+M2-TAMs in the tumor stroma significantly increased more than those in the normal mucosa stroma. Finally, generated M2 macrophages expressing HO-1 significantly resisted to oxidative stress induced by H2O2 in comparison with generated M0 macrophages. Taken together, our results suggested that an increased frequency of M2-TAMs infiltration in the CRC-TME is related to Nrf2-HO-1 axis mediated resistance to oxidative stress.
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Affiliation(s)
- Misato Ito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan.
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Katsuharu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Takahiro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomohiro Kikuchi
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hisashi Onozawa
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shotaro Fujita
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Wataru Sakamoto
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Zenichiro Saze
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
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Ito M, Mimura K, Nakajima S, Saito K, Min AKT, Okayama H, Saito M, Momma T, Saze Z, Ohtsuka M, Yamamoto T, Kono K. Immune escape mechanism behind resistance to anti-PD-1 therapy in gastrointestinal tract metastasis in malignant melanoma patients with multiple metastases. Cancer Immunol Immunother 2022; 71:2293-2300. [PMID: 35094125 DOI: 10.1007/s00262-022-03154-z] [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: 07/26/2021] [Accepted: 01/11/2022] [Indexed: 11/28/2022]
Abstract
Immunotherapy targeting the PD-1 axis has recently become a standard treatment for patients with malignant melanoma. However, approximately 25% of reported malignant melanoma patients who initially responded to immunotherapy with anti-PD-1 mAb had progressive disease, and the immune escape mechanism behind resistance to anti-PD-1 therapy is not yet fully understood in the clinical setting. In the present study, we included four malignant melanoma patients, in whom multiple metastases other than gastrointestinal tract metastasis had disappeared or were controlled under multidisciplinary treatment that included anti-PD-1 therapy. Using IHC, we evaluated the immune status of surgically resected specimens of gastrointestinal tract metastases as acquired resistant lesion to anti-PD-1 therapy. We herein report that the down-regulated expression of HLA class I and up-regulated expression of inhibitory immune checkpoint ligands, CD155 (ligand for T cell immunoglobulin and ITIM domain, TIGIT) and carcinoembryonic antigen-related adhesion molecule-1 (ligand for TIM-3), were observed on the tumor cells in the metastatic gastrointestinal tract tumors. Moreover, our results also suggest that stromal TGF-β may be related to this down-regulation of HLA class I expression on the tumor cells. In conclusion, it is likely that the down-regulated expression of HLA class I and additional expression of inhibitory immune checkpoint ligands other than PD-L1 on the tumor cells were acquired in the gastrointestinal tract metastasis during anti-PD-1 therapy in the malignant melanoma patients.
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Affiliation(s)
- Misato Ito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan.
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan.
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Katsuharu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Aung Kyi Thar Min
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Zenichiro Saze
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Mikio Ohtsuka
- Department of Dermatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Toshiyuki Yamamoto
- Department of Dermatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
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Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy. Cancers (Basel) 2022; 14:cancers14174261. [PMID: 36077799 PMCID: PMC9454990 DOI: 10.3390/cancers14174261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/28/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
While immune checkpoint (IC) therapies, particularly those targeting the PD-1/PD-L1 axis, have revolutionized the treatment of melanoma and several other cancers, their effect remains very limited in colorectal cancer (CRC). To define a comprehensive landscape of ICs in the human CRC tumor microenvironment (TME), we evaluated, using multiparametric flow cytometry, their ex vivo expression via tumor-infiltrating lymphocytes (TILs) (n = 40 CRCs) as well as that of their respective ligands on tumor and myeloid cells (n = 29). Supervised flow cytometry analyses showed that (i) most CD3+ TILs expressed PD-1 and TIGIT and, to a lesser extent, Tim-3, Lag3 and NKG2A, and (ii) EpCAM+ tumor cells and CD11b+ myeloid cells differed in their IC ligand expression profile, with a strikingly high expression of CD155 by tumor cells. An in situ analysis of IC and their ligands using immunohistochemistry on paraffin sections of CRC confirmed the overexpression of TIGIT and its ligand, CD155, in the TME. Most interestingly, an unsupervised clustering analysis of IC co-expression on CD4+ and CD8+ TILs identified two tumor subgroups, named IChigh and IClow. Altogether, our findings highlight the TIGIT/CD155 axis as a potential target that could be used in combination IC therapy in CRC.
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Peng Y, Qiu B, Tan F, Xu J, Bie F, He H, Liu L, Tian H, Bai G, Zhou B, Li Y, Huai Q, Yang Z, Gao S. TIGIT/CD47 dual high expression predicts prognosis and is associated with immunotherapy response in lung squamous cell carcinoma. Thorac Cancer 2022; 13:2014-2023. [PMID: 35611464 PMCID: PMC9284170 DOI: 10.1111/1759-7714.14478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/01/2022] [Accepted: 05/02/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Recent studies indicated that T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) and cluster of differentiation 47 (CD47) have emerged as new potential immunotherapy targets. However, the roles of TIGIT and CD47 in lung squamous cell carcinoma (LUSC) have not been fully illustrated. METHODS The specimens and clinicopathological information from 190 LUSC patients who underwent surgeries in our center were retrospectively collected. Immunohistochemical staining for TIGIT and CD47 was conducted. Transcriptional and clinical data of 479 LUSC were downloaded from The Cancer Genome Atlas (TCGA). RESULTS In the TCGA LUSC cohort, 142 (29.6%) cases were TIGIT/CD47 dual high expression at RNA level. The expression levels of TIGIT and CD47 were significantly correlated (p < 0.001). The proportions of patients with high TIGIT expression (p = 0.001) and high TIGIT/CD47 dual high expression (p = 0.049) were both higher in female cases. Advanced TNM stage (p = 0.006) and TIGIT/CD47 dual high expression (p = 0.047) were independent prognostic factors for LUSC. In the 190 LUSC cohort of our center, 75 (39.5%) cases were TIGIT/CD47 dual high expression at protein level. Cross-table analysis showed a correlation between TIGIT and CD47 expression. Older age (p = 0.001), advanced TNM stage (p < 0.001) and TIGIT/CD47 dual high expression (p = 0.046) were independent prognostic factors in our cohort. CONCLUSION We found that TIGIT and CD47 dual high expression was associated with poor prognosis in LUSC. We speculated that patients with dual high expression of CD47/TIGIT might be suitable for new target immunotherapy in the future.
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Affiliation(s)
- Yue Peng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Bin Qiu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Fengwei Tan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Jiachen Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
- Guangdong Provincial People's Hospital/Guangdong Provincial Academy of Medical SciencesGuangdong Provincial Key Lab of Translational Medicine in Lung CancerGuangzhouChina
| | - Fenglong Bie
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Huayu He
- Department of Thoracic SurgeryPeking University Third HospitalBeijingChina
| | - Lei Liu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Guangyu Bai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Bolun Zhou
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yuan Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Qilin Huai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Zhenlin Yang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
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Xu Y, Cao C, Zhu Z, Wang Y, Tan Y, Xu X. Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients. Front Genet 2022; 13:901734. [PMID: 35734431 PMCID: PMC9208084 DOI: 10.3389/fgene.2022.901734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/25/2022] [Indexed: 12/24/2022] Open
Abstract
Hypoxia, a typical hallmark of numerous tumors, indicates poor infiltration of antitumor lymphocytes, as well as facilitates the development, progression, and drug resistance of malignant cells. Here, the present research was performed to identify novel hypoxia-related molecular markers and their correlation to the tumor immune microenvironment (TIME) in colon cancer. The expression of hypoxia-related gene signature was extracted from The Cancer Genome Atlas (TCGA) COAD cohort. Based on this signature, a risk score model was constructed using the Lasso regression model. Its discrimination ability and stability were validated in another independent cohort (GSE17536) from Gene Expression Omnibus (GEO) database. Moreover, molecular biology experiments (quantitative real-time PCR and multiple immunohistochemistry) were performed to validate the results of bioinformatics analyses. Three hub genes, including PPFIA4, SERPINE1, and STC2, were chosen to build the risk score model. All of these genes were increasingly expressed in the hypoxia subgroup (HS). Compared with the normoxia subgroup (NS), HS had worse pathological features (T, N, M, and stage) and overall survival (OS), more expression of immune checkpoint molecules, poorer infiltration of some pro-inflammation immune cells (CD4+ T cells and CD8+ T cells), and enriched infiltration of M0/M2 macrophages. After the risk model was proven to be valuable and stable, a nomogram was built based on this model and some clinicopathological factors. Moreover, it had been identified that three hub genes were all increasingly expressed in hypoxic conditions by quantitative real-time PCR (qPCR). The results of multiple immunohistochemistry (mIHC) also showed that higher expression of hub genes was associated with poorer infiltration of pro-inflammation immune cells (CD8+ T cells and M1 macrophages) and richer infiltration of anti-inflammation immune cells (Treg cells and M2 macrophages). In conclusion, the present study uncovered the relations among hypoxia, TIME, and clinicopathological features of colon cancer. It might provide new insight and a potential therapeutic target for immunotherapy.
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Affiliation(s)
- Yixin Xu
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
- Department of General Surgery, Shanghai General Hospital of Nanjing Medical University, Shanghai, China
| | - Can Cao
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziyan Zhu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yibo Wang
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Yulin Tan
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
- *Correspondence: Xuezhong Xu, ; Yulin Tan,
| | - Xuezhong Xu
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
- *Correspondence: Xuezhong Xu, ; Yulin Tan,
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