Activin A Promotes Regulatory T-Cell-Mediated Immunosuppression In Irradiated Breast Cancer

Increased regulatory T cells (Treg) after radiotherapy have been reported, but the mechanisms of their induction remain incompletely understood. TOO is known to foster Treg differentiation within tumors and is activated following radiotherapy. Thus, we hypothesized that TGF beta blockade would result in decreased Tregs within the irradiated tumor microenvironment. We found increased Tregs in the tumors of mice treated with focal radiotherapy and TGF beta blockade. This increase was mediated by upregulation of another TGF beta family member, activin A. In vitro, activin A secretion was increased following irradiation of mouse and human breast cancer cells, and its expression was further enhanced upon TGF beta blockade. In vivo, dual blockade of activin A and TGF beta was required to decrease intratumoral Tregs in the context of radiotherapy. This resulted in an increase in CD8(+) T-cell priming and was associated with a reduced tumor recurrence rate. Combination of immune checkpoint inhibitors with the dual blockade of activin A and TGF beta led to the development of tumor-specific memory responses in irradiated breast cancer. Supporting the translational value of activin A targeting to reduce Treg-mediated immunosuppression, retrospective analysis of a public dataset of patients with breast cancer revealed a positive correlation between activin A gene expression and Treg abundance. Overall, these results shed light on an immune escape mechanism driven by activin A and suggest that dual targeting of activin A and TGF beta may be required to optimally unleash radiation-induced antitumor immunity against breast cancer.