TCR-V gamma delta usage distinguishes protumor from antitumor intestinal gamma delta T cell subsets

gamma delta T cells represent a substantial fraction of intestinal lymphocytes at homeostasis, but they also constitute a major lymphocyte population infiltrating colorectal cancers (CRCs); however, their temporal contribution to CRC development or progression remains unclear. Using human CRC samples and murine CRC models, we found that most gamma delta T cells in premalignant or nontumor colons exhibit cytotoxic markers, whereas tumor-infiltrating gamma delta T cells express a protumorigenic profile. These contrasting T cell profiles were associated with distinct T cell receptor (TCR)-V gamma delta gene usage in both humans and mice. Longitudinal intersectional genetics and antibody-dependent strategies targeting murine gamma delta T cells enriched in the epithelium at steady state led to heightened tumor development, whereas targeting gamma delta subsets that accumulate during CRC resulted in reduced tumor growth. Our results uncover temporal pro- and antitumor roles for gamma delta T cell subsets.