Abstract
Abstract TIGIT is an immune-checkpoint receptor mainly expressed on activated and memory T cells, regulatory T cells (Tregs), and NK cells. Engaged with CD155 and CD112, TIGIT can transmit an inhibitory signal that negatively regulate the cell functionality. TIGIT blockade antibodies that release the inhibitory signals and direct potent tumor killing are currently under active development. However, animal models appropriate for preclinical evaluation of human TIGIT antibodies are still largely unmet. To solve this problem, we established a TIGIT humanized mouse model (hTIGIT) in which the extracellular domain of mTIGIT was replaced with human counterparts while the trans-membrane and cytoplasmic domain kept intact. These hTIGIT mice express similar level of chimeric TIGIT as compared to mTIGIT in wildtype mice. Surprisingly, the growth of subcutaneously engrafted CT26 tumor in BALB/c-hTIGIT mice, but not MC38 tumor in B6-hTIGIT mice, was strongly inhibited when treated with human TIGIT antibody (anti-TIGIT). TILs analysis on CT26 engrafted BALB/c-hTIGIT revealed significantly higher levels of intra-tumoral NK and Treg cells, and more interesting, Treg was remarkably deleted after anti-TIGIT intervention. Furthermore, Fc mutation that blocks ADCC effect completely abolished its therapeutic activity. These data suggested that tumor infiltrated Treg clearance by ADCC may contribute to the tumor inhibition observed in BALB/c-hTIGIT model. Taken together, BALB/c-hTIGIT mouse is a novel non-human animal model that can recapitulate the tumor environment and appropriate for direct preclinical efficacy study of human TIGIT antibodies. Citation Format: Cunxiang Ju, Mingkun Zhang, Xiaoliu Yang, Song Li, Hongyan Sun, Shuai Li, Jing Tang, Jing Zhao, Xiang Gao. TIGIT humanized BALB/c mouse: A novel animal model for preclinical studies of human TIGIT antibodies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3256.
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