Yang et al. developed a cross-species (human and mouse) anti-TIGIT antibody (T4 Ab) that blocks TIGIT-CD155 interaction, and demonstrated that Fc-mediated effector function was responsible for its antitumor activity in CT26 and A20 tumor models. T4 Ab reduced tumor growth in a CD8+ T cell- and NK cell-dependent manner and reduced Foxp3+CD4+ Tregs in tumors via NK cell-mediated effector function. T4 Ab treatment induced durable antitumor immune memory and showed CD8+ T cell-mediated cross-tumor immune memory in CT26 and A20 tumors via a shared GSW11 endogenous retroviral antigen.
Contributed by Shishir Pant
ABSTRACT: The T cell immunoreceptor with Ig and ITIM domains (TIGIT) has been shown to exert inhibitory roles in antitumor immune responses. In this study, we report the development of a human mAb, T4, which recognizes both human and mouse TIGIT and blocks the interaction of TIGIT with its ligand CD155 in both species. The T4 Ab targets the segment connecting F and G strands of TIGIT's extracellular IgV domain, and we show in studies with mouse tumor models that the T4 Ab exerts strong antitumor activity and induces durable immune memory against various tumor types. Mechanistically, we demonstrate that the T4 Ab's antitumor effects are mediated via multiple immunological impacts, including a CD8(+) T immune response and Fc-mediated effector functions, through NK cells that cause significant reduction in the frequency of intratumoral T regulatory cells (Tregs). Notably, this Treg reduction apparently activates additional antitumor CD8(+) T cell responses, targeting tumor-shared Ags that are normally cryptic or suppressed by Tregs, thus conferring cross-tumor immune memory. Subsequent engineering for Fc variants of the T4 Ab with enhanced Fc-mediated effector functions yielded yet further improvements in antitumor efficacy. Thus, beyond demonstrating the T4 Ab as a promising candidate for the development of cancer immunotherapies, our study illustrates how the therapeutic efficacy of an anti-TIGIT Ab can be improved by enhancing Fc-mediated immune effector functions. Our insights about the multiple mechanisms of action of the T4 Ab and its Fc variants should help in developing new strategies that can realize the full clinical potential of anti-TIGIT Ab therapies.
Author Info: (1) College of Biological Sciences, China Agricultural University, Beijing 100193, China. National Institute of Biological Sciences, Beijing 102206, China. (2) National Institute o
Author Info: (1) College of Biological Sciences, China Agricultural University, Beijing 100193, China. National Institute of Biological Sciences, Beijing 102206, China. (2) National Institute of Biological Sciences, Beijing 102206, China. Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China. (3) National Institute of Biological Sciences, Beijing 102206, China. Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China. (4) National Institute of Biological Sciences, Beijing 102206, China. Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China. (5) National Institute of Biological Sciences, Beijing 102206, China. (6) National Institute of Biological Sciences, Beijing 102206, China. Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, College of Life Sciences, Peking University, Beijing 100871, China; and. (7) National Institute of Biological Sciences, Beijing 102206, China. (8) National Institute of Biological Sciences, Beijing 102206, China. (9) National Institute of Biological Sciences, Beijing 102206, China. Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China. (10) National Institute of Biological Sciences, Beijing 102206, China; suijianhua@nibs.ac.cn. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
