Arcus Biosciences, Hayward, California.
START San Antonio, San Antonio, Texas.
Cancer Res. 2024 Jun 14;84(12):1978-1995. doi: 10.1158/0008-5472.CAN-23-2455.
T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor.
Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.
T 细胞免疫受体含有免疫球蛋白和免疫受体酪氨酸抑制基序结构域（TIGIT）是免疫细胞上的一种抑制性受体，它与激活受体 CD226 竞争共享配体。肿瘤浸润淋巴细胞在调节性 T 细胞（Treg）和具有肿瘤反应性或耗竭表型的 CD8+T 细胞上表达 TIGIT 和 CD226，这支持了通过治疗性靶向 TIGIT 来增强抗肿瘤免疫的潜力。为了优化针对 TIGIT 的治疗性抗体的疗效，有必要了解 IgG Fc（Fcγ）受体结合对治疗的益处。在这项研究中，我们表明，在小鼠中联合使用 Fc 增强（Fce）或 Fc 沉默（Fcs）抗 TIGIT 与抗程序性细胞死亡蛋白 1，可通过不同的机制增强对肿瘤的控制：Fce 抗 TIGIT 促进肿瘤内 Treg 的耗竭，而 Fcs 抗 TIGIT 则不会。尽管保持 Treg 数量不变，Fcs 抗 TIGIT 以依赖淋巴结的方式增强了肿瘤特异性耗竭 CD8+群体的激活。Fce 抗 TIGIT 在体外诱导针对人 Treg 的抗体依赖性细胞介导的细胞毒性，并且在接受 Fce 抗 TIGIT 治疗的 I 期实体瘤癌症患者的外周血中测量到 Treg 显著减少。相比之下，Fcs 抗 TIGIT 未在体外耗尽人 Treg，并且在两名接受 Fcs 抗 TIGIT 治疗的 I 期实体瘤癌症患者中出现了轶事性的客观临床反应，这两名患者的外周 Treg 频率在治疗过程中保持稳定。总的来说，这些数据为缺乏结合 Fcγ 受体能力的抗 TIGIT 抗体的药理活性和抗肿瘤疗效提供了证据。
Fcs 沉默的抗 TIGIT 抗体增强了肿瘤特异性预耗竭 T 细胞的激活，并促进了抗肿瘤疗效，而不会耗尽 T 调节细胞。
