γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors

Lynch and colleagues characterize & gamma;& delta; T cells in colorectal and endometrial cancer and identify distinct subsets with opposing cytotoxic and wound healing functions, leading them to develop an expansion method that enhances cytotoxic functions. & gamma;& delta; T cells are important tissue-resident, innate T cells that are critical for tissue homeostasis. & gamma;& delta; cells are associated with positive prognosis in most tumors; however, little is known about their heterogeneity in human cancers. Here, we phenotyped innate and adaptive cells in human colorectal (CRC) and endometrial cancer. We found striking differences in & gamma;& delta; subsets and function in tumors compared to normal tissue, and in the & gamma;& delta; subsets present in tumor types. In CRC, an amphiregulin (AREG)-producing subset emerges, while endometrial cancer is infiltrated by cytotoxic cells. In humanized CRC models, tumors induced this AREG phenotype in V & delta;1 cells after adoptive transfer. To exploit the beneficial roles of & gamma;& delta; cells for cell therapy, we developed an expansion method that enhanced cytotoxic function and boosted metabolic flexibility, while eliminating AREG production, achieving greater tumor infiltration and tumor clearance. This method has broad applications in cellular therapy as an 'off-the-shelf' treatment option.