Fc-silent anti-TIGIT antibodies potentiate anti-tumor immunity without depleting regulatory T cells

Cancer Res. 2024 Apr 18. doi: 10.1158/0008-5472.CAN-23-2455. Online ahead of print.ABSTRACTTIGIT 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 anti-tumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand whether there is therapeutic benefit from Fcγ receptor (FcγR) binding. Here, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with anti-PD-1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated 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 Phase I solid tumor cancer patients 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 Phase I solid tumor cancer patients in whom peripheral Treg frequencies remained stable on treatment....
Source: Cell Research - Category: Cytology Authors: Source Type: research