Characteristics and significance of γδ T cells in colorectal cancer

Abstract

Gamma-delta T cells are a subset of T cells that have features of both innate and adaptive immunity. Their role in cancer remains controversial, since both anti- and protumor functions have been reported. We aimed to shed light on the distinct characteristics of γδ T cells in colorectal cancer (CRC). In two independent cohorts, including 1 687 CRC patients, we identified γδ and αβ T cells with multiplex immunohistochemistry to evaluate their prognostic significance. To further analyze the characteristics of γδ T cells, we utilized single-cell RNA sequencing data of 62 CRC patients. High γδ T cell densities were associated with prolonged survival in both cohorts, and this association was independent of other tumor and patient characteristics in Cohort 1, where the multivariable HR for high (vs. low) γδ T cell density was 0.65 (95% CI 0.47-0.90), while the corresponding HR in Cohort 2 was 0.82 (0.50-1.33). αβ T cells demonstrated a stronger association with longer survival that was independent of other prognostic factors in both cohorts. γδ T cells were enriched in mismatch repair (MMR) deficient and BRAF mutated tumors. Single-cell RNA sequencing analysis revealed that γδ T cells were abundant in tumors with weak antigen presentation signaling in tumor cells. Immunohistochemically, high γδ T cell densities were associated with beta-2 microglobulin loss independent of MMR status. These findings indicate that γδ T cells are associated with prolonged survival in CRC and are concentrated in tumors with impaired antigen presentation and MMR deficiency.