Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer

  • Nat Commun. 2023 Mar 13;14(1):1390. doi: 10.1038/s41467-023-37096-6.
Jeffrey Patterson-Fortin  1  2 ,  Heta Jadhav  1 ,  Constantia Pantelidou  1  3 ,  Tin Phan  4 ,  Carter Grochala  4  5 ,  Anita K Mehta  6  7 ,  Jennifer L Guerriero  6 ,  Gerburg M Wulf  8 ,  Brian M Wolpin  1  2  9 ,  Ben Z Stanger  10 ,  Andrew J Aguirre  1  2  9 ,  James M Cleary  1  2  9 ,  Alan D D'Andrea  4  11 ,  Geoffrey I Shapiro  12  13  14
Affiliations
  • 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 2. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
  • 3. Bayer Pharmaceuticals, Cambridge, MA, USA.
  • 4. Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA.
  • 5. Arpeggio, Boulder, CO, USA.
  • 6. Department of Surgical Oncology and Harvard Medical School, Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • 7. Sanofi, Cambridge, MA, USA.
  • 8. Department of Medicine, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
  • 9. Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 10. Department of Medicine, Division of Gastroenterology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
  • 11. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 12. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. [email protected].
  • 13. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. [email protected].
  • 14. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. [email protected].
PMID: 36914658 DOI: 10.1038/s41467-023-37096-6
Abstract

Recently developed inhibitors of polymerase theta (POLθ) have demonstrated synthetic lethality in BRCA-deficient tumor models. To examine the contribution of the immune microenvironment to antitumor efficacy, we characterized the effects of POLθ inhibition in immunocompetent models of BRCA1-deficient triple-negative breast Cancer (TNBC) or BRCA2-deficient pancreatic ductal adenocarcinoma (PDAC). We demonstrate that genetic POLQ depletion or pharmacological POLθ inhibition induces both innate and adaptive immune responses in these models. POLθ inhibition resulted in increased micronuclei, cGAS/STING pathway activation, type I interferon gene expression, CD8+ T cell infiltration and activation, local paracrine activation of dendritic cells and upregulation of PD-L1 expression. Depletion of CD8+ T cells compromised the efficacy of POLθ inhibition, whereas antitumor effects were augmented in combination with anti-PD-1 immunotherapy. Collectively, our findings demonstrate that POLθ inhibition induces immune responses in a cGAS/STING-dependent manner and provide a rationale for combining POLθ inhibition with immune checkpoint blockade for the treatment of HR-deficient cancers.

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