| ID | 62992 |
| FullText URL | |
| Author |
Kawashima, Shusuke
Research Institute, Chiba Cancer Center
Inozume, Takashi
Research Institute, Chiba Cancer Center
Kawazu, Masahito
Research Institute, Chiba Cancer Center
Ueno, Toshihide
Division of Cellular Signaling, National Cancer Center Research Institute
Nagasaki, Joji
Research Institute, Chiba Cancer Center
Tanji, Etsuko
Research Institute, Chiba Cancer Center
Honobe, Akiko
Department of Dermatology, University of Yamanashi
Ohnuma, Takehiro
Department of Dermatology, University of Yamanashi
Kawamura, Tatsuyoshi
Department of Dermatology, University of Yamanashi
Umeda, Yoshiyasu
Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center
Nakamura, Yasuhiro
Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center
Kawasaki, Tomonori
Department of Pathology, Saitama Medical University International Medical Center
Kiniwa, Yukiko
Department of Dermatology, Shinshu University School of Medicine
Yamasaki, Osamu
Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Kaken ID
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Fukushima, Satoshi
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University
Ikehara, Yuzuru
Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine
Mano, Hiroyuki
Division of Cellular Signaling, National Cancer Center Research Institute
Suzuki, Yutaka
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo
Nishikawa, Hiroyoshi
Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center
Matsue, Hiroyuki
Department of Dermatology, Chiba University Graduate School of Medicine
Togashi, Yosuke
Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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| Abstract | Background
Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. Methods We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. Results Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance. Conclusions The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer. |
| Published Date | 2021-11
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| Publication Title |
Journal for ImmunoTherapy of Cancer
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| Volume | volume9
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| Issue | issue11
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| Publisher | BMJ
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| Start Page | e003134
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| ISSN | 2051-1426
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| Content Type |
Journal Article
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| language |
English
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| OAI-PMH Set |
岡山大学
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| Copyright Holders | © Author(s) (or their employer(s)) 2021.
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| File Version | publisher
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| DOI | |
| Web of Science KeyUT | |
| Related Url | isVersionOf https://doi.org/10.1136/jitc-2021-003134
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| License | https://creativecommons.org/licenses/by/4.0/
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| Citation | Kawashima S, Inozume T, Kawazu M, et al. TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment. Journal for ImmunoTherapy of Cancer 2021;9:e003134. doi:10.1136/jitc-2021-003134
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