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Cancer Immunology Research
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Research Articles

Activin A Promotes Regulatory T-cell–Mediated Immunosuppression in Irradiated Breast Cancer

Mara De Martino, Camille Daviaud, Julie M. Diamond, Jeffrey Kraynak, Amandine Alard, Silvia C. Formenti, Lance D. Miller, Sandra Demaria and Claire Vanpouille-Box
Mara De Martino
1Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.
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Camille Daviaud
1Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.
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Julie M. Diamond
1Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.
2Department of Pathology, New York University School of Medicine, New York, New York.
3Endless Frontier Labs, New York, New York.
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Jeffrey Kraynak
1Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.
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Amandine Alard
4Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
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Silvia C. Formenti
1Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.
5Sandra and Edward Meyer Cancer Center, New York, New York.
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Lance D. Miller
6Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina.
7Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Sandra Demaria
1Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.
5Sandra and Edward Meyer Cancer Center, New York, New York.
8Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
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Claire Vanpouille-Box
1Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.
5Sandra and Edward Meyer Cancer Center, New York, New York.
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  • For correspondence: clv2002@med.cornell.edu
DOI: 10.1158/2326-6066.CIR-19-0305 Published January 2021
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Abstract

Increased regulatory T cells (Treg) after radiotherapy 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 radiotherapy. Thus, we hypothesized that TGFβ 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 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 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 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 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 TGFβ may be required to optimally unleash radiation-induced antitumor immunity against breast cancer.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:89–102

  • Received May 4, 2019.
  • Revision received September 1, 2020.
  • Accepted October 14, 2020.
  • Published first October 22, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (1)
January 2021
Volume 9, Issue 1
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Activin A Promotes Regulatory T-cell–Mediated Immunosuppression in Irradiated Breast Cancer
Mara De Martino, Camille Daviaud, Julie M. Diamond, Jeffrey Kraynak, Amandine Alard, Silvia C. Formenti, Lance D. Miller, Sandra Demaria and Claire Vanpouille-Box
Cancer Immunol Res January 1 2021 (9) (1) 89-102; DOI: 10.1158/2326-6066.CIR-19-0305

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Activin A Promotes Regulatory T-cell–Mediated Immunosuppression in Irradiated Breast Cancer
Mara De Martino, Camille Daviaud, Julie M. Diamond, Jeffrey Kraynak, Amandine Alard, Silvia C. Formenti, Lance D. Miller, Sandra Demaria and Claire Vanpouille-Box
Cancer Immunol Res January 1 2021 (9) (1) 89-102; DOI: 10.1158/2326-6066.CIR-19-0305
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