T cell–intrinsic VISTA expression promotes resistance to CTLA-4 blockade by restricting CD8⁺ T cell responses

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Abstract

V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint protein that impairs antitumor T cell responses. While broadly expressed on myeloid cells and T cells, the specific contribution of T cell–intrinsic VISTA to antitumor immunity remains undefined. This study investigated the phenotypic and functional consequences of T cell–specific VISTA deletion in tumor-specific CD8+ T cells. Single-cell transcriptomic analysis, TCR repertoire profiling, and flow cytometry revealed that loss of T cell–intrinsic VISTA enhanced early priming and short-term expansion of CD8+ T cells, yet this initial advantage failed to confer durable tumor control. Persistent dysfunction in VISTA-deficient T cells was in part driven by trans-VISTA on myeloid cells, while CTLA-4 upregulation further constrained T cell responses. T cell–intrinsic VISTA deficiency cooperated with CTLA-4 blockade to improve T cell survival and broaden TCR repertoire diversity, resulting in more robust tumor regression than CTLA-4 inhibition alone. A transcriptional signature enriched in VISTA-deficient cytotoxic T cells correlated with favorable outcomes in cancer patients treated with existing immune checkpoint inhibitors. These findings collectively define T cell–intrinsic mechanisms by which VISTA enforces T cell dysfunction and underscore its potential as both a therapeutic target and a biomarker of resistance to current immunotherapies.

Authors

Cassandra Gilmour, Elizabeth DeLaney, Prerana B. Parthasarathy, Dia Roy, Hieu M. Ta, Amin Zakeri, Paolo Elguera Grandez, Sachin Patnaik, Keman Zhang, Ivan Juric, Rahul Rangan, Zahraa Al-Hilli, Anthony Tufaro, Booki Min, Samuel E. Weinberg, Timothy A. Chan, Natalie L. Silver, Stefanie Avril, Tyler Alban, Li Lily Wang