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

Abstract

Innate-like tissue-resident γδ 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 γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αβ T cells required TCR signaling. A comparable population of Vδ1+ 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 Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αβ TCRs. However, whereas in most cases TCRαβ repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αβ T cells.

Cancer immunotherapy with γδ T cells: many paths ahead of us

“…Vδ1 TILs in breast cancer were shown to suppress αβ T cells, 104 whereas a recent study actually identified innate-like Vδ1 TILs as being associated with remission in triple-negative breast cancer. 106 We conclude that the protumorigenic potential of γδ T cells must be well taken into account; however, there is a substantial body of evidence supporting the notion that γδ T cells are exceptional candidates for cellular immunotherapy.…”

Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial γδ T cell compartments

“…γδ T cells, particularly those residing within extralymphoid tissues, have been increasingly implicated in the regulation of tissue maintenance and protection against cancer [39][40][41][42][43][44] . Nonetheless, the cells' biologies remain poorly elucidated.…”

Human γδ TCR Repertoires in Health and Disease

“…The distribution of TCR repertoires proposed that presumably lung-infiltrating Vδ1 + T cells underwent an adaptive-like clonal expansion during active tuberculosis [92]. In contrast, tissue-resident NKG2D + and CD69 + Vδ1 + T cells were reported to have oligoclonal TCR repertoires in healthy breast tissues that remained stable after tumor-infiltration, consistent with their innate-like features such as NKG2D-driven activation [108,109].…”