提吉特
CD8型
抗体
癌症研究
免疫学
免疫系统
细胞毒性T细胞
受体
医学
体外
生物
内科学
生物化学
作者
Dana Piovesan,Amber E. de Groot,Soonweng Cho,Amy E. Anderson,Rebecca D. Ray,Amita Patnaik,Paul Foster,Casey G. Mitchell,Alejandra Y. Lopez Espinoza,Wandi S. Zhu,Carlo E. Stagnaro,Hema Singh,Xiaoning Zhao,Lisa Seitz,Nigel P. Walker,Matthew J. Walters,Kelsey E. Sivick
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-04-18
卷期号:84 (12): 1978-1995
标识
DOI:10.1158/0008-5472.can-23-2455
摘要
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.
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