γδ T-cell Receptors Derived from Breast Cancer-Infiltrating T Lymphocytes Mediate Antitumor Reactivity

gamma delta T cells in human solid tumors remain poorly defined. Here, we describe molecular and functional analyses of T-cell receptors (TCR) from tumor-infiltrating gamma delta T lymphocytes (gamma delta TIL) that were in direct contact with tumor cells in breast cancer lesions from archival material. We observed that the majority of gamma delta TILs harbored a proinflammatory phenotype and only a minority associated with the expression of IL17. We characterized TCR gamma or TCR delta chains of gamma delta TILs and observed a higher proportion of V delta 2(+) T cells compared with other tumor types. By reconstructing matched V delta 2(-) TCR gamma and TCR delta pairs derived from single-cell sequencing, our data suggest that gd TILs could be active against breast cancer and other tumor types. The reactivity pattern against tumor cells depended on both the TCR gamma and TCR delta chains and was independent of additional costimulation through other innate immune receptors. We conclude that gamma delta TILs can mediate tumor reactivity through their individual gamma delta TCR pairs and that engineered T cells expressing TCR gamma and delta chains derived from gamma delta TILs display potent antitumor reactivity against different cancer cell types and, thus, may be a valuable tool for engineering immune cells for adoptive cell therapies.