An IL6-Adenosine Positive Feedback Loop between CD73+ γδTregs and CAFs Promotes Tumor Progression in Human Breast Cancer

The tumor microenvironment induces immunosuppression via recruiting and expanding suppressive immune cells such as regulatory T cells (Treg) to promote cancer progression. In this study, we documented that tumor-infiltrating CD73(+) gamma delta Tregs were the predominant Tregs in human breast cancer and exerted more potent immunosuppressive activity than CD4(+) or CD8(+) Tregs. We further demonstrated that cancer-associated fibroblast (CAF)-derived IL6, rather than TGF beta 1, induced CD73(+) gdTreg differentiation from paired normal breast tissues via the IL6/STAT3 pathway to produce more adenosine and become potent immunosuppressive T cells. CD73(+) gamma delta Tregs could in turn promote IL6 secretion by CAFs through adenosine/A2BR/p38MAPK signaling, thereby forming an IL6-adenosine positive feedback loop. CD73(+) gamma delta Treg infiltration also impaired the tumoricidal functions of CD8(+) T cells and significantly correlated with worse prognosis of patients. The data indicate that the IL6-adenosine loop between CD73(+) gamma delta Tregs and CAFs is important to promote immunosuppression and tumor progression in human breast cancer, which may be critical for tumor immunotherapy.