Oncolytic virus-mediated p53 overexpression promotes immunogenic cell death and efficacy of PD-1 blockade in pancreatic cancer

Hiroyuki Araki, Hiroshi Tazawa, Nobuhiko Kanaya, Yoshinori Kajiwara, Motohiko Yamada, Masashi Hashimoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Yuzo Umeda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Research output: Contribution to journalArticlepeer-review

Abstract

Immune checkpoint inhibitors, including anti-programmed cell death 1 (PD-1) antibody, provide improved clinical outcome in certain cancers. However, pancreatic ductal adenocarcinoma (PDAC) is refractory to PD-1 blockade therapy due to poor immune response. Oncolytic virotherapy is a novel approach for inducing immunogenic cell death (ICD). We demonstrated the therapeutic potential of p53-expressing telomerase-specific oncolytic adenovirus OBP-702 to induce ICD and anti-tumor immune responses in human PDAC cells with different p53 status (Capan-2, PK-59, PK-45H, Capan-1, MIA PaCa-2, BxPC-3) and murine PDAC cells (PAN02). OBP-702 significantly enhanced ICD with secretion of extracellular adenosine triphosphate and high-mobility group box protein B1 by inducing p53-mediated apoptosis and autophagy. OBP-702 significantly promoted the tumor infiltration of CD8+ T cells and the anti-tumor efficacy of PD-1 blockade in a subcutaneous PAN02 syngeneic tumor model. Our results suggest that oncolytic adenovirus-mediated p53 overexpression augments ICD and the efficacy of PD-1 blockade therapy against cold PDAC tumors. Further in vivo experiments would be warranted to evaluate the survival benefit of tumor-bearing mice in combination therapy with OBP-702 and PD-1 blockade.

Original languageEnglish
Pages (from-to)3-13
Number of pages11
JournalMolecular Therapy - Oncolytics
Volume27
DOIs
Publication statusPublished - Dec 15 2022

Keywords

  • immunogenic cell death
  • oncolytic adenovirus
  • p53
  • pancreatic cancer
  • PD-1 blockade

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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