TY - JOUR
T1 - TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment
AU - Kawashima, Shusuke
AU - Inozume, Takashi
AU - Kawazu, Masahito
AU - Ueno, Toshihide
AU - Nagasaki, Joji
AU - Tanji, Etsuko
AU - Honobe, Akiko
AU - Ohnuma, Takehiro
AU - Kawamura, Tatsuyoshi
AU - Umeda, Yoshiyasu
AU - Nakamura, Yasuhiro
AU - Kawasaki, Tomonori
AU - Kiniwa, Yukiko
AU - Yamasaki, Osamu
AU - Fukushima, Satoshi
AU - Ikehara, Yuzuru
AU - Mano, Hiroyuki
AU - Suzuki, Yutaka
AU - Nishikawa, Hiroyoshi
AU - Matsue, Hiroyuki
AU - Togashi, Yosuke
N1 - Funding Information:
Funding This study was supported by Grants-in-Aid for Scientific Research (B grant no. no. 20H03694 (YT), C grant no. 19K08744 (TI), and Challenging Exploratory Research no. 19K22574 (YT)) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Project for Cancer Research and Therapeutic Evolution (P-CREATE, no. 18cm0106340h0001 (YT), no. 20cm0106502h0005 (MK), and no. 21cm0106383 (YT)); Practical Research for
Funding Information:
Female C57BL/6J mice (6–8 weeks old) were purchased from CLEA Japan (Tokyo, Japan). C57BL/6J-Prkdc<scid>/Rbrc mice (B6 SCID; RBRC01346) were provided by RIKEN BRC (Tsukuba, Japan) through the National BioResource Project of the MEXT/AMED, Japan. Cells (1×106) were injected subcutaneously, and the tumor volume was monitored two times a week. The mean values of the long and short diameters were used to generate tumor growth curves. Mice were grouped when the tumor volume reached approximately 100 mm3, and ICIs (anti-PD-1 mAb, 200 µg/mouse; anti-CTLA-4 mAb,
Funding Information:
Innovative Cancer Control (19ck0106521h0001 (YT)) from the Japan Agency for Medical Research and Development (AMED); the Fusion Oriented Research for disruptive Science and Technology (FOREST, no. 21-211033868 (YT)) from Japan Science and Technology Agency (JST); the Chiba Prefecture Research Grant (YT); the Naito Foundation (YT); the Takeda Science Foundation (YT); the Mitsubishi Foundation (YT); the Tokyo Biochemical Research Foundation (YT); the Daiichi Sankyo Foundation (YT); the Foundation for Promotion of Cancer Research in Japan (YT); the Mochida Memorial Foundation (YT); the Japanese Foundation for Multidisciplinary Treatment of Cancer Foundation (YT); the KANAE Foundation for the Promotion of Medical Science (YT); the Yasuda Memorial Foundation for Medicine (YT); the MSD Life Science Foundation (YT); the Kowa Life Science Foundation (YT); the Senri Life Science Foundation (YT); and the Uehara Memorial Foundation (YT). Competing interests TI received honoraria and research grants from Ono Pharmaceutical, Bristol Myers Squibb, and MSD outside of this study. YN received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, MSD, and Taiho Pharmaceutical outside of this study. HMan served as a board member of CureGene, and received research grants from Ono Pharmaceutical, Daiichi-Sankyo, PFDeNA, and Konica Minolta outside of this study. HN received research grants and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, MSD and Bristol Myers Squibb, and research grants from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma and BD Japan outside of this study. YT received research grants from KOTAI Biotechnologies, Daiichi-Sankyo, Ono Pharmaceutical, Bristol Myers Squibb, KORTUC, and honoraria from Ono Pharmaceutical, Bristol Myers Squibb, AstraZeneca, Chugai Pharmaceutical, and MSD outside of this study. All other authors declare that they have no competing financial interests.
Publisher Copyright:
©
PY - 2021/11/18
Y1 - 2021/11/18
N2 - 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.
AB - 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.
KW - combination
KW - costimulatory and inhibitory t-cell receptors
KW - drug therapy
KW - immunotherapy
KW - melanoma
KW - tumor microenvironment
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U2 - 10.1136/jitc-2021-003134
DO - 10.1136/jitc-2021-003134
M3 - Article
C2 - 34795004
AN - SCOPUS:85120352697
SN - 2051-1426
VL - 9
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 11
M1 - 003134
ER -
