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

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Science Immunology  21 Jun 2019:
Vol. 4, Issue 36, eaaw2004
DOI: 10.1126/sciimmunol.aaw2004

Using cell death to resurrect antitumor immunity

Dying cells can trigger activation of the immune system. Here, Snyder et al. have engineered cells that can be induced to undergo necroptotic cell death. By injecting these cells directly into tumors, they have examined the ability of these dying cells to promote antitumor responses in situ and at a distant site harboring syngeneic tumor. In addition to promoting immune response in situ, these injected cells drove a systemic immune response driven by conventional dendritic cells 1 (cDC1s) and CD8+ T cells that promoted regression of tumor at the distant site as well. Most impressively, they found that the dying cells did not have to express tumor-specific antigens to promote antitumor immunity.


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.

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