Effector Vδ1 γδT cells mediate anti-tumor immunity and are reprogrammed by imatinib in human gastrointestinal stromal tumor

Gamma-delta (γδ) T cells are emerging effectors of anti-tumor immunity, but their relevance to gastrointestinal stromal tumor, the most common human sarcoma, is not defined. Here, we integrate single-cell transcriptomics, immunophenotypic and T cell receptor profiling, and functional assays of circulating and intratumoral γδ T cells across 68 human GIST specimens. Vδ1 cells predominated within tumors, and their abundance correlated with improved outcomes across 3 separate patient cohorts. γδ T cells from untreated tumors were cytotoxic ex vivo, but tumors that had become resistant to the tyrosine kinase inhibitor imatinib had lower Vδ1 composition, effector function, and altered clonality, and were enriched for apoptosis, IL-17 signaling, and checkpoint pathways. In a genetically engineered murine GIST model, PD-L1 blockade enhanced imatinib efficacy and restored tumor γδ T cell function. Thus, γδ T cells contribute to tumor immunity in GIST and are reprogrammed during imatinib resistance, making them an attractive immunotherapy target.