Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes

Nature Communications
Lien Van HoeckeXavier Saelens

Abstract

Cancer immunotherapy can induce durable antitumor responses. However, many patients poorly respond to such therapies. Here we describe a generic antitumor therapy that is based on the intratumor delivery of mRNA that codes for the necroptosis executioner mixed lineage kinase domain-like (MLKL) protein. This intervention stalls primary tumor growth and protects against distal and disseminated tumor formation in syngeneic mouse melanoma and colon carcinoma models. Moreover, MLKL-mRNA treatment combined with immune checkpoint blockade further improves the antitumor activity. MLKL-mRNA treatment rapidly induces T cell responses directed against tumor neo-antigens and requires CD4+ and CD8+ T cells to prevent tumor growth. Type I interferon signaling and Batf3-dependent dendritic cells are essential for this mRNA treatment to elicit tumor antigen-specific T cell responses. Moreover, MLKL-mRNA treatment blunts the growth of human lymphoma in mice with a reconstituted human adaptive immune system. MLKL-based treatment can thus be exploited as an effective antitumor immunotherapy.

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Citations

Apr 3, 2019·The Journal of Gene Medicine·Jiayan WuXuesi Chen
Jan 5, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tania Løve AaesPeter Vandenabeele
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Jan 19, 2021·ACS Biomaterials Science & Engineering·Hui LiZhiyue Zhang

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Methods Mentioned

BETA
transfection
flow cytometry
transgenic
exome sequencing
PCR
electrophoresis

Software Mentioned

GraphPad Prism
FlowJo
Living Image
FACS Diva

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