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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of

Jeffrey Patterson-Fortin1,2, Heta Jadhav1, Constantia Pantelidou1,3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Nature Communications
|March 14, 2023
PubMed

Insights

Polymerase theta (POLθ) inhibitors trigger immune responses in BRCA-deficient cancers. Combining POLθ inhibition with immunotherapy enhances antitumor effects, offering a new treatment strategy for HR-deficient tumors.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Genetics

Background:

  • Polymerase theta (POLθ) inhibitors show synthetic lethality in BRCA-deficient tumors.
  • The role of the immune microenvironment in POLθ inhibitor efficacy is not well understood.

Purpose of the Study:

  • To investigate the impact of POLθ inhibition on immune responses in BRCA-deficient triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) models.
  • To evaluate the potential of combining POLθ inhibition with immune checkpoint blockade.

Main Methods:

  • Utilized genetic POLQ depletion and pharmacological POLθ inhibition in immunocompetent TNBC and PDAC models.
  • Assessed innate and adaptive immune responses, including cGAS/STING pathway activation, cytokine expression, T cell infiltration and activation, and PD-L1 upregulation.
  • Investigated the role of CD8+ T cells and combined POLθ inhibition with anti-PD-1 immunotherapy.

Main Results:

  • POLθ inhibition induced significant innate and adaptive immune responses.
  • Observed increased micronuclei, cGAS/STING activation, type I interferon expression, CD8+ T cell infiltration/activation, dendritic cell activation, and PD-L1 upregulation.
  • CD8+ T cell depletion reduced efficacy, while combination with anti-PD-1 augmented antitumor effects.

Conclusions:

  • POLθ inhibition stimulates anti-tumor immunity via the cGAS/STING pathway.
  • Combination therapy of POLθ inhibition with immune checkpoint blockade is a promising strategy for HR-deficient cancers.

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