Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity.

1. Sci Immunol. 2019 Jun 21;4(36):eaaw2004. doi: 10.1126/sciimmunol.aaw2004. Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity. Snyder AG(1), Hubbard NW(1), Messmer MN(1), Kofman SB(1), Hagan CE(1), Orozco SL(1)(2), Chiang K(2), Daniels BP(3), Baker D(4), Oberst A(5). Author information: (1)Department of Immunology, University of Washington, Seattle, WA 98109, USA. (2)Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA. (3)Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA. (4)Institute for Protein Design, University of Washington, Seattle, WA 98109, USA. (5)Department of Immunology, University of Washington, Seattle, WA 98109, USA. oberst@uw.edu. Although the signaling events that induce different forms of programmed cell death are well defined, the subsequent immune responses to dying cells in the context of cancer remain relatively unexplored. Necroptosis occurs downstream of the receptor-interacting protein kinases RIPK1 and RIPK3, whose activation leads to lytic cell death accompanied by de novo production of proinflammatory mediators. Here, we show that ectopic introduction of necroptotic cells to the tumor microenvironment promotes BATF3+ cDC1- and CD8+ leukocyte-dependent antitumor immunity accompanied by increased tumor antigen loading by tumor-associated antigen-presenting cells. Furthermore, we report the development of constitutively active forms of the necroptosis-inducing enzyme RIPK3 and show that delivery of a gene encoding this enzyme to tumor cells using adeno-associated viruses induces tumor cell necroptosis, which synergizes with immune checkpoint blockade to promote durable tumor clearance. These findings support a role for RIPK1/RIPK3 activation as a beneficial proximal target in the initiation of tumor immunity. Considering that successful tumor immunotherapy regimens will require the rational application of multiple treatment modalities, we propose that maximizing the immunogenicity of dying cells within the tumor microenvironment through specific activation of the necroptotic pathway represents a beneficial treatment approach that may warrant further clinical development. Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. DOI: 10.1126/sciimmunol.aaw2004 PMCID: PMC6831211 PMID: 31227597 [Indexed for MEDLINE] Conflict of interest statement: Competing interests: The testing of necroptosis-inducing AAVs was supported in part by funds received from FivePrime Therapeutics as part of a sponsored research agreement; AO has acted as a paid consultant for FivePrime Therapeutics. AGS, NWH, and AO are inventors on a pending patent held by the University of Washington for the constitutively-oligomerizing cell death enzymes described in this manuscript.