Abstract LB036: TIGIT blockade promotes intratumoral Treg cells with less suppressive and more effector-like phenotype to support antitumor responses

Abstract Therapeutic checkpoint blockade of TIGIT (T cell immunoreceptor with Ig and ITIM domains) in combination with PD-1/PD-L1 pathway blockade has been shown to eradicate large established tumors in preclinical mouse models by enhancing anti-tumor cytotoxic CD8+ T cell responses. In addition to CD8+ T cells, TIGIT is also expressed on other immune cells, with particularly high expression on immunosuppressive regulatory T (Treg) cells. Here, we explored the functional consequences of TIGIT blockade on Treg cells in syngeneic mouse tumor models. In contrast to treatment with Fc-active anti-CTLA-4 which significantly reduced Treg cell frequencies and numbers in tumors, Treg cells were modestly reduced or even increase in tumors with Fc-active anti-TIGIT, indicating that anti-TIGIT was not driving depletion of the bulk Treg cell population. Treg cells had reduced suppressive characteristics and increased effector-like properties, suggesting modulation of the Treg cell phenotype by TIGIT blockade. This effect on Treg cell phenotype was dependent on Fc competency of the anti-TIGIT antibody as well as CD226, the activating counterreceptor to TIGIT. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) demonstrated that anti-TIGIT altered the epigenetic and transcriptional regulatory programs involved in generation and maintenance of suppressive Treg cells. Single-cell RNA sequencing (scRNAseq) revealed four distinct Treg cell clusters and provided resolution of the gene expression shifts away from suppressive function mediated by anti-TIGIT. Our data demonstrate that co-blockade of TIGIT and PD-1 reprograms Treg cells from a pro-tumor immunosuppressive phenotype to an anti-tumor effector-like cell that participates in the response against tumors. Citation Format: Eugene Chiang, Ellen Duong, Karl Banta, Sunny Wu, Thomas Wu, Katie Nutsch, Lili Adams, Stephanie Mittman, Yan Qu, Ira Mellman. TIGIT blockade promotes intratumoral Treg cells with less suppressive and more effector-like phenotype to support antitumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB036.