Dysfunctional tumor-infiltrating Vδ1+T lymphocytes in microsatellite-stable colorectal cancer

Although gamma delta T cells are known to participate in immune dysregulation in solid tumors, their relevance to human microsatellite-stable (MSS) colorectal cancer (CRC) is still undefined. Here, using integrated gene expression analysis and T cell receptor sequencing, we characterized gamma delta T cells in MSS CRC, with a focus on V delta 1 + T cells. We identified V delta 1+ T cells with shared motifs in the third complementarity-determining region of the delta-chain, reflective of antigen recognition. Changes in gene and protein expression levels suggested a dysfunctional effector state of V delta 1+ T cells in MSS CRC, distinct from V delta 1+ T cells in microsatellite-instable (MSI). Interaction analysis highlighted an immunosuppressive role of fibroblasts in the dysregulation of V delta 1+ T cells in MSS CRC via the TIGIT-NECTIN2 axis. Blocking this pathway with a TIGIT antibody partially restored cytotoxicity of the dysfunctional V delta 1 phenotype. These results define an operative pathway in gamma delta T cells in MSS CRC. Although gamma delta T cells are known to participate in immune dysregulation in solid tumors, their relevance to human microsatellite-stable (MSS) colorectal cancer (CRC) is less well-studied. Here, using single-cell RNA-sequencing, the authors identify a V delta 1 + T cell subset, which are functionally impaired in MSS CRC via a TIGIT-NECTIN2 interaction.