RETRACTED ARTICLE: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer

Jeffrey Patterson-Fortin, Heta Jadhav, Constantia Pantelidou, Tin Phan, Carter Grochala, Anita K. Mehta, Jennifer L. Guerriero, Gerburg M. Wulf, Brian M. Wolpin, Ben Z. Stanger, Andrew J. Aguirre, James M. Cleary, Alan D. D’Andrea and Geoffrey I. Shapiro ()
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Jeffrey Patterson-Fortin: Dana-Farber Cancer Institute
Heta Jadhav: Dana-Farber Cancer Institute
Constantia Pantelidou: Dana-Farber Cancer Institute
Tin Phan: Dana-Farber Cancer Institute and Harvard Medical School
Carter Grochala: Dana-Farber Cancer Institute and Harvard Medical School
Anita K. Mehta: Brigham and Women’s Hospital
Jennifer L. Guerriero: Brigham and Women’s Hospital
Gerburg M. Wulf: Beth Israel Deaconess Medical Center and Harvard Medical School
Brian M. Wolpin: Dana-Farber Cancer Institute
Ben Z. Stanger: University of Pennsylvania Perelman School of Medicine
Andrew J. Aguirre: Dana-Farber Cancer Institute
James M. Cleary: Dana-Farber Cancer Institute
Alan D. D’Andrea: Dana-Farber Cancer Institute and Harvard Medical School
Geoffrey I. Shapiro: Dana-Farber Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37096-6

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