Renal cell carcinoma-infiltrating Vd1 and Vd2 gd T Cells are distinct from blood-circulating Vd1 and Vd2 gd T Cells 9186

Abstract Description γδ T cells are classified into Vδ1, Vδ2, and other less common subsets. Vγ9Vδ2 T cells predominantly circulate in blood, responding to phosphoantigens via butyrophilins and infiltrating inflamed tissues including cancers. Vδ1 T cells, largely tissue-resident, expand in response to stress-related antigens. In cancer, both Vδ1 and Vδ2 T cells infiltrate into tumors. In this study, we investigated the immunologic phenotypes and TCR repertoires of blood and cancer-infiltrating γδ T cells from 50 patients. Cancer-infiltrating Vδ1 and Vδ2 γδ T cells were phenotypically different from each other and also distinct from respective blood counterparts. Cancer-infiltrating Vδ2 T cells express NKG2A, CD16, and CCR5 at levels similar to those in blood Vδ2 T cells. In contrast, cancer-infiltrating Vδ1 T cells expressed higher levels of CD45RO and CCR5 than blood Vδ1 T cells. Whereas cancer-infiltrating Vδ2 T cells expressed NKG2A and CD94, cancer-infiltrating Vδ1 T cells expressed different sets of KIRs, not NKG2A. Single-cell NGS analysis identified distinct sub-populations of cancer-infiltrating γδ T cells, characterized by unique Vγ chains, cytotoxic markers, cytokine receptors, KIRs, and transcription factors. This diversity of cancer-infiltrating γδ T cells contributes to both anti-cancer and pro-cancer properties, highlighting the necessity to understand their antigenic and functional roles for developing effective γδ T cell-based cancer immunotherapies. Funding Sources Supported by 2023R1A2C2004510; RS-2024-00405650 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)