Phosphoantigens Overcome Human TCRVγ9+ γδ Cell Immunosuppression by TGF-β: Relevance for Cancer Immunotherapy

Abstract

Human γδ cells expressing TCRVγ9 are HLA-unrestricted CTLs with high relevance for cancer immunotherapy. Many tumor cell types produce TGF-β, however, a cytokine strongly immunosuppressive for conventional T CD4, CD8, and NK cells. Whether TGF-β also inhibits TCRVγ9+ lymphocytes was unknown. Because phosphoantigens (PAgs), such as bromohydrin pyrophosphate, selectively activate the antitumor functions of TCRVγ9+ T cells, in this study, we investigated whether TGF-β modulates these functions. We report that TGF-β does not block activation of TCRVγ9+ T cells but inhibits their PAg/IL-2–induced proliferation and maturation into effector cells and finally reduces the cytotoxic activity of these γδ T cells when exposed to lymphoma target cells. TGF-β did not bias their differentiation pattern toward γδ Th17 or γδ regulatory T cells. Nevertheless, increasing doses of PAg stimulus countered TGF-β inhibition. So, although TGF-β impairs TCRVγ9+ γδ cells like other cytolytic lymphocytes, PAg alone or combined to therapeutic mAb has the ability to bypass its immunosuppressive activity.