College of Biological Sciences, China Agricultural University, Beijing 100193, China.
National Institute of Biological Sciences, Beijing 102206, China.
J Immunol. 2020 Oct 15;205(8):2156-2168. doi: 10.4049/jimmunol.1901413. Epub 2020 Sep 4.
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.
T 细胞免疫受体含有免疫球蛋白和 ITIM 结构域（TIGIT）已被证明在抗肿瘤免疫反应中发挥抑制作用。在这项研究中，我们报告了一种人源单克隆抗体 T4 的开发，该抗体识别人和小鼠的 TIGIT 并阻断 TIGIT 与其配体 CD155 在两种物种中的相互作用。T4 Ab 靶向 TIGIT 胞外 IgV 结构域的 F 和 G 链连接段，我们在小鼠肿瘤模型研究中表明，T4 Ab 发挥强大的抗肿瘤活性，并诱导针对各种肿瘤类型的持久免疫记忆。从机制上讲，我们证明 T4 Ab 的抗肿瘤作用是通过多种免疫影响介导的，包括 CD8 T 免疫反应和通过 NK 细胞介导的 Fc 效应功能，导致肿瘤内调节性 T 细胞（Tregs）频率显著降低。值得注意的是，这种 Treg 减少显然会激活额外的抗肿瘤 CD8 T 细胞反应，靶向肿瘤共享的抗原，这些抗原通常是隐匿的或被 Tregs 抑制，从而赋予交叉肿瘤免疫记忆。随后对 T4 Ab 的 Fc 变体进行工程改造，增强了 Fc 介导的效应功能，进一步提高了抗肿瘤疗效。因此，除了证明 T4 Ab 是开发癌症免疫疗法的有前途的候选药物外，我们的研究还说明了如何通过增强 Fc 介导的免疫效应功能来提高抗 TIGIT Ab 的治疗效果。我们对 T4 Ab 及其 Fc 变体的多种作用机制的见解应有助于开发新的策略，从而实现抗 TIGIT Ab 疗法的全部临床潜力。
