De Martino et al. showed that irradiation of murine and human breast cancer cell lines induced secretion of activin A, which synergized with TGFβ to induce co-cultured naive CD4+ T cells to express CD25 and Foxp3 Treg markers. Anti-TGFβ treatment of mice bearing murine breast tumors expressing an activin A silencing RNA decreased focal radiation-induced Tregs intratumorally, increased CD8+ T cell priming, reduced tumor recurrence synergistically with anti-PD-1 or anti-CTLA-4, and reduced tumor-specific memory with anti-CTLA-4. Analysis of TCGA data showed that activin A gene expression correlates with patients’ tumor-infiltrating Treg scores.

Contributed by Paula Hochman

ABSTRACT: Increased regulatory T cells (Tregs) after radiation therapy have been reported, but the mechanisms of their induction remain incompletely understood. TGFβ is known to foster Treg differentiation within tumors and is activated following radiation therapy. Thus, we hypothesized that TGFβ blockade would result in decreased Tregs within the irradiated tumor microenvironment (TME). We found increased Tregs in the tumors of mice treated with focal radiotherapy and TGFβ blockade. This increase was mediated by upregulation of another TGFβ 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 TGFβ blockade. In vivo, dual blockade of activin A and TGFβ was required to decrease intratumoral Tregs in the context of radiation. 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 TGFβ 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 breast cancer patients 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 TGFβ may be required to optimally unleash radiation-induced antitumor immunity against breast cancer.

Author Info: (1) Department of Radiation Oncology, Weill Cornell Medicine. (2) Department of Radiation Oncology, Weill Cornell Medicine. (3) Pathology, NYU Laura and Isaac Perlmutter Cancer Cen

Author Info: (1) Department of Radiation Oncology, Weill Cornell Medicine. (2) Department of Radiation Oncology, Weill Cornell Medicine. (3) Pathology, NYU Laura and Isaac Perlmutter Cancer Center. (4) Department of Radiation Oncology, Weill Cornell Medicine. (5) Tumor biology, CRCT Inserm. (6) Department of Radiation Oncology, Weill Cornell Medicine. (7) Cancer Biology, Wake Forest University School of Medicine. (8) Department of Radiation Oncology, Weill Cornell Medicine. (9) Department of Radiation Oncology, Weill Cornell Medicine clv2002@med.cornell.edu.