Oncolytic Parapoxvirus induces Gasdermin E-mediated pyroptosis and activates antitumor immunity

Jing Lin, Shihui Sun, Kui Zhao, Fei Gao, Renling Wang, Qi Li, Yanlong Zhou, Jing Zhang, Yue Li, Xinyue Wang, Le Du, Shuai Wang, Zi Li, Huijun Lu, Yungang Lan, Deguang Song, Wei Guo, Yujia Chen, Feng Gao, Yicheng Zhao, Rongrong Fan, Jiyu Guan () and Wenqi He ()
Additional contact information
Jing Lin: Jilin University
Shihui Sun: Jilin University
Kui Zhao: Jilin University
Fei Gao: Jilin University
Renling Wang: Jilin University
Qi Li: Jilin University
Yanlong Zhou: Jilin University
Jing Zhang: Jilin University
Yue Li: Jilin University
Xinyue Wang: Jilin University
Le Du: Jilin University
Shuai Wang: Jilin University
Zi Li: Jilin University
Huijun Lu: Jilin University
Yungang Lan: Jilin University
Deguang Song: Jilin University
Wei Guo: The first hospital of Jilin University
Yujia Chen: The first hospital of Jilin University
Feng Gao: Jilin University
Yicheng Zhao: Changchun University of Chinese Medicine
Rongrong Fan: Karolinska Institutet
Jiyu Guan: Jilin University
Wenqi He: Jilin University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The advantage of oncolytic viruses (OV) in cancer therapy is their dual effect of directly killing tumours while prompting anti-tumour immune response. Oncolytic parapoxvirus ovis (ORFV) and other OVs are thought to induce apoptosis, but apoptosis, being the immunogenically inert compared to other types of cell death, does not explain the highly inflamed microenvironment in OV-challenged tumors. Here we show that ORFV and its recombinant therapeutic derivatives are able to trigger tumor cell pyroptosis via Gasdermin E (GSDME). This effect is especially prominent in GSDME-low tumor cells, in which ORFV-challenge pre-stabilizes GSDME by decreasing its ubiquitination and subsequently initiates pyroptosis. Consistently, GSDME depletion reduces the proportion of intratumoral cytotoxic T lymphocytes, pyroptotic cell death and the success of tumor ORFV virotherapy. In vivo, the OV preferentially accumulates in the tumour upon systemic delivery and elicits pyroptotic tumor killing. Consequentially, ORFV sensitizes immunologically ‘cold’ tumors to checkpoint blockade. This study thus highlights the critical role of GSDME-mediated pyroptosis in oncolytic ORFV-based antitumor immunity and identifies combinatorial cancer therapy strategies.

Date: 2023
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DOI: 10.1038/s41467-023-35917-2

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