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

Lien Van Hoecke (UGent) , Sandra Van Lint (UGent) , Kenny Roose (UGent) , Alexander Van Parys (UGent) , Peter Vandenabeele (UGent) , Johan Grooten (UGent) , Jan Tavernier (UGent) , Stefaan De Koker (UGent) and Xavier Saelens (UGent)
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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.
Keywords
MIXED LINEAGE KINASE, IMMUNOGENIC CELL-DEATH, DOMAIN-LIKE PROTEIN, CANCER-THERAPY, DENDRITIC CELLS, CALRETICULIN EXPOSURE, ANTI-PD-L1 ANTIBODY, MELANOMA, DOWNSTREAM, ACTIVATION

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Chicago
Van Hoecke, Lien, Sandra Van Lint, Kenny Roose, Alexander Van Parys, Peter Vandenabeele, Johan Grooten, Jan Tavernier, Stefaan De Koker, and Xavier Saelens. 2018. “Treatment with mRNA Coding for the Necroptosis Mediator MLKL Induces Antitumor Immunity Directed Against Neo-epitopes.” Nature Communications 9.
APA
Van Hoecke, L., Van Lint, S., Roose, K., Van Parys, A., Vandenabeele, P., Grooten, J., Tavernier, J., et al. (2018). Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes. NATURE COMMUNICATIONS, 9.
Vancouver
1.
Van Hoecke L, Van Lint S, Roose K, Van Parys A, Vandenabeele P, Grooten J, et al. Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes. NATURE COMMUNICATIONS. 2018;9.
MLA
Van Hoecke, Lien, Sandra Van Lint, Kenny Roose, et al. “Treatment with mRNA Coding for the Necroptosis Mediator MLKL Induces Antitumor Immunity Directed Against Neo-epitopes.” NATURE COMMUNICATIONS 9 (2018): n. pag. Print.
@article{8572154,
  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.},
  articleno    = {3417},
  author       = {Van Hoecke, Lien and Van Lint, Sandra and Roose, Kenny and Van Parys, Alexander and Vandenabeele, Peter and Grooten, Johan and Tavernier, Jan and De Koker, Stefaan and Saelens, Xavier},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  language     = {eng},
  pages        = {17},
  title        = {Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes},
  url          = {http://dx.doi.org/10.1038/s41467-018-05979-8},
  volume       = {9},
  year         = {2018},
}

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