STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer

Constantia Pantelidou; Heta Jadhav; Aditi Kothari; Renyan Liu; Gerburg M Wulf; Jennifer L Guerriero; Geoffrey I Shapiro

doi:10.1038/s41523-022-00471-5

STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer

NPJ Breast Cancer. 2022 Sep 6;8(1):102. doi: 10.1038/s41523-022-00471-5.

Authors

Constantia Pantelidou^{1

2}, Heta Jadhav¹, Aditi Kothari¹, Renyan Liu¹, Gerburg M Wulf^{3

4}, Jennifer L Guerriero^{4

5

6}, Geoffrey I Shapiro^{7

8

9}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Bayer Pharmaceuticals, Cambridge, MA, USA.
³ Department of Medicine, Division of Hematology-Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
⁴ Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, USA.
⁵ Breast Tumor Immunology Laboratory, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. geoffrey_shapiro@dfci.harvard.edu.
⁸ Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, USA. geoffrey_shapiro@dfci.harvard.edu.
⁹ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. geoffrey_shapiro@dfci.harvard.edu.

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors exert their efficacy via synthetic lethal effects and by inducing cGAS/STING-mediated immune responses. We demonstrate that compared to monotherapies, combined PARP inhibition and STING agonism results in increased STING pathway activation, greater cytotoxic T-cell recruitment and enhanced dendritic cell activation in BRCA1-deficient breast cancer models. The combination markedly improved anti-tumor efficacy in vivo, with evidence of complete tumor clearance, prolongation of survival and induction of immunologic memory.

Grants and funding

P50 CA168504/CA/NCI NIH HHS/United States