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

• DOI: 10.1136/jitc-2021-003134
• Publication Date: 2021-11-18T16:35:41Z
• Authors: Shusuke Kawashima; Takashi Inozume; Masahito Kawazu; Toshihide Ueno; Joji Nagasaki; Etsuko Tanji; Akiko Honobe; Takehiro Ohnuma; Tatsuyoshi Kawamura; Yoshiyasu Umeda; Yasuhiro Nakamura; Tomonori Kawasaki; Yukiko Kiniwa; Osamu Yamasaki; Satoshi Fukushima; Yuzuru Ikehara; Hiroyuki Mano; Yutaka Suzuki; Hiroyoshi Nishikawa; Hiroyuki Matsue; Yosuke Togashi
• Keywords: TIGIT

Background Patients with cancer benefit from treatment immune checkpoint inhibitors (ICIs), and those an inflamed tumor microenvironment (TME) and/or high mutation burden (TMB), particularly, tend to respond ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the TME TMB. We assessed detailed biological mechanisms of ICIs such as programmed death 1 cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. Methods established four pairs autologous cell lines tumor-infiltrating lymphocytes (TILs) melanoma treated ICIs. These TILs were subjected comprehensive analyses in vitro functional assays. volume vivo mouse models validate identified mechanism. Furthermore, we analyzed additional samples another large cohort. Results Two super-responders, acquired resistance: first patient had a non-inflamed due loss beta-2 microglobulin gene, other having extremely TMB which are reportedly predictive biomarkers. Tumor line paired TIL showed CD155, TIGIT ligand, expression T cells, respectively. or CD155-deletion activated cells assay this patient. CD155 increased surviving coculturing responder, suppressed + T-cell activation. Consistently, could aid overcoming models. In samples, was related TME, including both primary resistance. Conclusions The TIGIT/CD155 axis mediates promoting development cancer.