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PARP Inhibitors Differentially Regulate Immune Responses in Distinct Genetic Backgrounds of High-Grade Serous

Luiza Doro Pereira1, Monica Wielgos-Bonvallet1, Selim Misirlioglu1

  • 1Division of Gynecologic Oncology, Department of OB/GYN, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York.

Cancer Research Communications
|January 24, 2025
PubMed

Insights

Different poly(ADP-ribose) polymerase inhibitors (PARPi) impact ovarian cancer cell immune gene expression. Talazoparib upregulates key immune genes in both HRD and HR proficient HGSC cells, unlike veliparib, offering insights for combining PARPi with immune checkpoint inhibitors.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint inhibitors (ICIs) show limited efficacy in ovarian cancer.
  • Combining ICIs with poly(ADP-ribose) polymerase inhibitors (PARPi) is under investigation to improve outcomes.
  • Understanding the immunomodulatory effects of different PARPi is crucial for optimizing combination therapies.

Purpose of the Study:

  • To compare the immunomodulatory effects of talazoparib and veliparib in ovarian cancer cell lines.
  • To investigate the impact of PARPi on immune-related gene expression in homologous recombination deficient (HRD) and proficient high-grade serous tubo-ovarian carcinoma (HGSC) cells.
  • To elucidate the mechanisms by which PARPi influence the tumor immune microenvironment.

Main Methods:

  • Treatment of HGSC cell lines (OVCAR3, CAOV3, COV361, OVCAR8) with talazoparib, veliparib, and olaparib.
  • Analysis of immune-related gene expression, including CXCL8, IL-6, TNF, and CXCL10.
  • Assessment of the role of the cGAS-STING pathway in mediating PARPi effects.

Main Results:

  • Talazoparib upregulated CXCL8, IL-6, and TNF in both HRD and HR proficient HGSC cell lines.
  • Veliparib showed similar effects only in an HRD HGSC cell line model.
  • Differences were observed in CXCL10 modulation between PARP trappers and veliparib, independent of the cGAS-STING pathway.

Conclusions:

  • Talazoparib exhibits broader immunomodulatory effects compared to veliparib in ovarian cancer cells.
  • PARPi differentially affect immune gene expression based on their mechanism of action and cellular genetic background.
  • These findings provide mechanistic insights for selecting optimal PARPi partners for ICI combination therapy in ovarian cancer.

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