Dysfunctional tumor-infiltrating Vδ1+ T lymphocytes in MSS colorectal cancer

Impairment and exhaustion of effector functions limiting a proper immune response have been reported for conventional T cells in chronic infection and cancer. However, the functional relevance of γδ T cells influenced by the tumor microenvironment in human colorectal cancer (CRC) is still unclear. Here, we identify and characterize a distinct population of Vδ1+ T cells in human microsatellite stable CRC. Using integrated gene expression analysis and ⍺β/γδ-T cell receptor sequencing, we demonstrate activated adaptive immune responses in Vδ1+ T cells in CRC, which are accompanied by perturbances of innate immunity. However, enhanced upregulation of exhaustion genes, altered effector and cell stress molecules in Vδ1+ T cells pinpoint to impaired γδ T cells in CRC compared to distant healthy colon. Cellular interaction analysis highlights a role of cancer-associated fibroblasts in the dysregulation of Vδ1+ T cells in CRC. Immunophenotyping identified a distinct population of Vδ1+ T cells which dominates the γδ T cell subsets and displays a functionally impaired phenotype with a potential to be restored in vitro. These results define pathways operative in γδ T cells in CRC and provide a roadmap for harnessing γδ T cells for specific immunotherapeutic strategies.