TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment.

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

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.

Informations de copyright

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Déclaration de conflit d'intérêts

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.