To interrupt the interactions between the adhesin TIGIT (found on NK and T cells) and its primary ligand CD155 (PVR; a dysregulated adhesin found on many tumor cells), Shen, Fu, and Wei et al. tested human and mouse versions of a dimeric fusion of the extracellular domain of TIGIT to Ig-Fc (TIGIT-Fc). TIGIT-Fc demonstrated potent ADCC activity against multiple tumor lines and inhibition of Treg suppression in vitro. Alone and in combination with anti-PD-L1, TIGIT-Fc induced antitumor activity in xenograft models (with allogeneic human T cells) and in syngeneic tumor models. Activity was dependent on NK and CD4+ T cells, and generated immunological memory.
Contributed by Ed Fritsch
ABSTRACT: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a checkpoint receptor that mediates both T cell and natural killer (NK) cell exhaustion in tumors. An Fc-TIGIT fusion protein was shown to induce an immune-tolerance effect in a previous report, but the relevance of the TIGIT-Fc protein to tumor immunity is unknown. Here, we found that TIGIT-Fc promotes, rather than suppresses, tumor immunity. TIGIT-Fc treatment promoted the effector function of CD8+ T and NK cells in several tumor-bearing mouse models. TIGIT-Fc treatment resulted in potent T cell- and NK cell-mediated tumor reactivity, sustained memory-induced immunity in tumor re-challenge models, enhanced therapeutic effects via an antibody against PD-L1, and induction of Th1 development in CD4+ T cells. TIGIT-Fc showed a potent antibody-dependent cell-mediated cytotoxicity (ADCC) effect but had no intrinsic effect on tumor cell development. Our findings elucidate the role of TIGIT-Fc in tumor immune reprogramming, suggesting that TIGIT-Fc treatment alone or in combination with other checkpoint receptor blockers is a promising anticancer therapeutic strategy.
Author Info: (1) Department of Gastrointestinal Surgery, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University. (2) Department of Biophysics, Second Military Med
Author Info: (1) Department of Gastrointestinal Surgery, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University. (2) Department of Biophysics, Second Military Medical University. (3) Department of Biophysics, Second Military Medical University. (4) Department of Biophysics, Second Military Medical University. (5) Department of Biophysics, Second Military Medical University. (6) Department of Biophysics, Second Military Medical University. (7) Department of Biophysics, Second Military Medical University. (8) Department of Biophysics, Second Military Medical University hus@smmu.edu.cn.
