An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer

Innate-like tissue-resident gamma delta T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct gamma delta T cell compartment, primarily expressing T cell receptor (TCR) V delta 1 chains, by comparison to V delta 2 chains that predominate in peripheral blood. Breast-resident V delta 1(+) cells were functionally skewed toward cytolysis and IFN-gamma production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident V delta 1(+) cells could be activated innately via the NKG2D receptor, whereas neighboring CD8(+) alpha beta T cells required TCR signaling. A comparable population of V delta 1(+) cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with V delta 1(+) cell representation, but not with either total gamma delta T cells or V delta 2(+) T cells. As expected, progression-free survival also correlated with alpha beta TCRs. However, whereas in most cases TCR alpha beta repertoires focused, typical of antigen-specific responses, this was not observed for V delta 1(+) cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident V delta 1(+) compartments and adaptive responses mounted by alpha beta T cells.