CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.