Recombinant viruses delivering the necroptosis mediator MLKL induce a potent antitumor immunity in mice

ABSTRACT

Vaccinia viruses (VACV) are a novel class of immune-oncolytic therapeutics and their mechanism of action is based both on their capacity to replicate selectively in cancer cells and to elicit danger signals that can boost anti-tumor immunity. We recently reported that the intratumor expression of MLKL, a necroptosis inducing factor, generates a protective anti-tumor immunity. Here, we combined both approaches to test the use of VACV to deliver MLKL into the tumor. We generated VACV vectors expressing MLKL and evaluated the effects of MLKL on antitumor efficacy. In vitro infection of cancer cells with MLKL-expressing vectors led to cell death with necroptotic hallmarks. In syngeneic mouse tumor models, VACV expressing MLKL induced an outstanding antitumor activity, which was associated with a robust immunity directed against neo-epitopes. In conclusion, delivery of MLKL by VACV vectors boosts the intrinsic anti-tumor properties of these viral vectors by promoting in situ immunogenic cell death of infected cancer cells.

KEYWORDS:

• Immunotherapy
• necroptosis
• MLKL
• oncolytic virus
• VACV

Acknowledgments

This work was supported by Deutsche Krebs Hilfe project number 70112543 (JJR and GS), by a VIB Technology Transfer Fund project (XS), and by Spanish Ministry of Science I+D+i project number PID2019-109102RA-I00 (JJR). JJR is funded by the Spanish Ministry of Science through a Ramon y Cajal program (RYC2018-025425-I).

Declaration of interest statement

LVH and XS are named as inventors on patent application WO2019/048639, which claims IP rights on the use of MLKL for anti-tumor treatment.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the Ministerio de Ciencia e Innovación PID2019-109102RA-I00 and RYC2018-025425-I, Deutsche Krebs Hilfe 70112543, and VIB Technology Transfer Fund (no project number).