Related Experiment Video

Updated: Feb 2, 2026

Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
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Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer

Published on: January 17, 2025

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Sequential platinum and PARP Inhibition enhances PD1 immunotherapy efficacy in murine Brca2 mutated pancreatic cancer

John C McVey1,2, Max M Wattenberg1,3,4, Heather Coho1,3

  • 1Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Scientific Reports
|January 31, 2026
PubMed

Insights

BRCA-mutated pancreatic cancer (PDAC) shows promise with platinum chemotherapy and PARPi maintenance. Combining immunotherapy with PARPi maintenance therapy significantly improved outcomes in a preclinical model, suggesting a new treatment strategy for this aggressive cancer.

Area of Science:

  • Oncology
  • Cancer Biology
  • Immunotherapy

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a difficult cancer to treat.
  • BRCA-mutated PDAC is sensitive to DNA-damaging agents, leading to platinum-based chemotherapy and PARPi maintenance as standard care.
  • The POLO trial showed no overall survival benefit with olaparib, indicating a need for improved strategies and better preclinical models.

Purpose of the Study:

  • To develop a syngeneic, immunocompetent mouse model for BRCA-mutated PDAC.
  • To evaluate the efficacy of PARPi monotherapy and combination treatments in this model.
  • To investigate the impact of chemotherapy induction on PARPi response and the tumor microenvironment.

Main Methods:

  • Developed a syngeneic, immunocompetent mouse model of Brca2-mutated PDAC.
  • Assessed sensitivity to cisplatin/gemcitabine and PARPi monotherapy.
  • Investigated the effects of platinum-based chemotherapy induction followed by PARPi maintenance, with or without anti-PD1 therapy.

Main Results:

  • The model showed sensitivity to platinum-based chemotherapy but limited response to PARPi monotherapy.
  • Chemotherapy induction sensitized tumors to PARPi maintenance, creating a T cell-inflamed microenvironment.
  • Resistance to PARPi maintenance was linked to CDX2 expression and tumor differentiation.
  • Combining anti-PD1 therapy with PARPi maintenance significantly enhanced tumor regression and prolonged survival.

Conclusions:

  • Preclinical data support combining immunotherapy with PARPi maintenance for BRCA-mutated PDAC.
  • This combination strategy may overcome resistance and improve survival in homologous recombination-deficient PDAC.
  • The developed mouse model is a valuable tool for testing next-generation therapies.

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