Expression of GPX4 by oncolytic vaccinia virus can significantly enhance CD8+T cell function and its impact against pancreatic ductal adenocarcinoma

Oncoimmunology. 2024 Feb 27;13(1):2322173. doi: 10.1080/2162402X.2024.2322173. eCollection 2024.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is currently difficult to treat, even when therapies are combined with immune checkpoint blockade (ICB). A novel strategy for immunotherapy would be to maximize the therapeutic potential of oncolytic viruses (OVs), which have been proven to engage the regulation of tumor microenvironment (TME) and cause-specific T-cell responses. To boost tumor sensitivity to ICB therapy, this study aimed to investigate how glutathione peroxide 4 (GPX4)-loaded OVs affect CD8+ T cells and repair the immunosuppressive environment. Here, we successfully constructed a novel recombinant oncolytic vaccinia virus (OVV) encoding the mouse GPX4 gene. We found the OVV-GPX4 effectively replicated in tumor cells and prompted the expression of GPX4 in T cells. Our research indicated that OVV-GPX4 could reshape the TME, rectify the depletion of CD8+T cells, and enhance the antitumor effects of ICB therapy.

Keywords: Glutathione peroxide 4; oncolytic vaccinia virus; pancreatic ductal adenocarcinoma; tumor microenvironment.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / therapy
  • Mice
  • Oncolytic Virotherapy*
  • Oncolytic Viruses* / genetics
  • Pancreatic Neoplasms* / therapy
  • Tumor Microenvironment
  • Vaccinia virus / genetics

Substances

  • glutathione peroxidase 4, mouse

Grants and funding

This study was supported by the Foundation of Science Technology Department of Zhejiang Province [No. LGF22H080012, No. LGF22H080008], Zhejiang Provincial Medical Technology Plan Project [No. 2022KY505, No. 2020KY052].