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

Author

Listed:
  • Lien Van Hoecke

    (VIB
    Ghent University)

  • Sandra Van Lint

    (VIB
    Ghent University)

  • Kenny Roose

    (VIB
    Ghent University)

  • Alexander Van Parys

    (VIB
    Ghent University)

  • Peter Vandenabeele

    (Ghent University
    VIB)

  • Johan Grooten

    (Ghent University)

  • Jan Tavernier

    (VIB
    Ghent University)

  • Stefaan Koker

    (Ghent University)

  • Xavier Saelens

    (VIB
    Ghent University)

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.

Suggested Citation

  • Lien Van Hoecke & Sandra Van Lint & Kenny Roose & Alexander Van Parys & Peter Vandenabeele & Johan Grooten & Jan Tavernier & Stefaan Koker & Xavier Saelens, 2018. "Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05979-8
    DOI: 10.1038/s41467-018-05979-8
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    Cited by:

    1. Cheng-Yu Liao & Ge Li & Feng-Ping Kang & Cai-Feng Lin & Cheng-Ke Xie & Yong-Ding Wu & Jian-Fei Hu & Hong-Yi Lin & Shun-Cang Zhu & Xiao-Xiao Huang & Jian-Lin Lai & Li-Qun Chen & Yi Huang & Qiao-Wei Li , 2024. "Necroptosis enhances ‘don’t eat me’ signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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