Snyder et al. showed that when cells dying by necroptosis (tumor cells or NIH/3T3 fibroblasts) were introduced into murine tumors, they released NF-κB-dependent proinflammatory signals that enhanced antigen uptake and activation of BATF3+ cDC1s, which activated antitumor CD8+ T cell responses and mediated durable, systemic tumor control and increased survival. Delivery of a gene encoding a constitutively active form of the necroptosis-inducing enzyme RIPK3 induced similar effects and synergized with PD-1 checkpoint blockade to clear tumors in ~70% of mice. Based on TCGA data, high RIPK3 expression is associated with longer survival in a subset of patients.
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.
Author Info: (1) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (2) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (3) Department of Im
Author Info: (1) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (2) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (3) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (4) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (5) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (6) Department of Immunology, University of Washington, Seattle, WA 98109, USA. Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA. (7) Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA. (8) Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA. (9) Institute for Protein Design, University of Washington, Seattle, WA 98109, USA. (10) Department of Immunology, University of Washington, Seattle, WA 98109, USA. oberst@uw.edu.
