Regulatory T cells sabotage anti-tumor γδ T cells by creating IL-2-deficient environments

Regulatory T (Treg) cells are potent immunosuppressors of conventional αβ T cells in the tumor microenvironment, but how they may affect innate-like γδ T cells remains poorly understood. Here, we show that induced Treg depletion in mice selectively unleashes IFNγ-producing γδ T cells, which are required for tumor control in an orthotopic breast cancer model. Treg cells outcompete IFNγ+ γδ T cells for IL-2 due to increased expression of the high-affinity IL-2 receptor, thereby limiting the proliferation and effector functions of IFNγ+ γδ T cells. Consistently, in vivo neutralization of IL-2 alongside Treg depletion abrogates the induction of IFNγ+ γδ T cell responses, whereas administration of an IL-2Rβγc agonist circumvents Treg-mediated suppression and enhances tumor control. Finally, Treg cells also inhibit endogenous and expanded human γδ T-cells, which can be rescued by IL-2Rβγc agonism to enhance therapeutic responses in xenografted mice. Thus, bypassing Treg-mediated suppression may improve the outcome of γδ T cell-based immunotherapies.