期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 9, 期 11, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-003134
关键词
costimulatory and inhibitory t-cell receptors; drug therapy; combination; immunotherapy; melanoma; tumor microenvironment
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20H03694, 19K08744, 19K22574]
- Project for Cancer Research and Therapeutic Evolution (P-CREATE) [18cm0106340h0001, 20cm0106502h0005, 21cm0106383]
- Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) [19ck0106521h0001]
- Fusion Oriented Research for disruptive Science and Technology (FOREST) from Japan Science and Technology Agency (JST) [21-211033868]
- Chiba Prefecture Research Grant
- Naito Foundation
- Takeda Science Foundation
- Mitsubishi Foundation
- Tokyo Biochemical Research Foundation
- Daiichi Sankyo Foundation
- Foundation for Promotion of Cancer Research in Japan
- Mochida Memorial Foundation
- Japanese Foundation for Multidisciplinary Treatment of Cancer Foundation
- KANAE Foundation
- Yasuda Memorial Foundation
- MSD Life Science Foundation
- Kowa Life Science Foundation
- Senri Life Science Foundation
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [20H03694, 19K22574, 19K08744] Funding Source: KAKEN
Cancer patients benefit from treatment with immune checkpoint inhibitors, especially those with an inflamed tumor microenvironment or high tumor mutation burden. However, some patients develop resistance to ICIs. The TIGIT/CD155 axis has been identified as mediating resistance to ICIs in patients with melanoma with an inflamed TME, suggesting potential for developing TIGIT blockade therapies in this population.
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.
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