Dataset Information

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

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.

SUBMITTER: Wei W

PROVIDER: S-EPMC10900272 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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

Wei Wei W Tian Linqing L Zheng Xiaoyan X Zhong Lei L Chen Yuan Y Dong Hui H Zhang Guibing G Wang Shibing S Tong Xiangmin X

Oncoimmunology 20240227 1

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 C ...[more]

PMID: 38419758

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Project description:UnlabelledPancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3- and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas.ImportanceDespite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These results suggest that slightly pathogenic IAVs may prove to be effective for oncolytic virotherapy of PDA and provide grounds for further studies to develop specific and targeted viruses, with the aim of testing their efficacy in clinical contexts.

Dataset Information

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

Publications

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

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Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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