Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates anti-tumor immunity

• Published in: Science immunology 2019-06, Vol.4 (36)
• Main Authors: Snyder, Annelise G., Hubbard, Nicholas W., Messmer, Michelle N., Kofman, Sigal B., Hagan, Cassidy E., Orozco, Susana L., Chiang, Kristy, Daniels, Brian P., Baker, David, Oberst, Andrew
• Format: Article
• Language: English
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.aaw2004

Although the signaling events that induce different forms of programmed cell death (PCD) are well-defined, the downstream 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 pro-inflammatory mediators. Here, we show that ectopic introduction of necroptotic cells to the tumor microenvironment promotes BATF3 + cDC1- and CD8 + leukocyte-dependent anti-tumor 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 (AAVs) 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. Activation of the necroptotic signaling kinases RIPK1 and RIPK3 within the tumor microenvironment enhances cDC1- and CD8+ leukocyte-mediated anti-tumor immunity.