RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8 ⁺ T cells

Abstract

Dying cells initiate adaptive immunity by providing both antigens and inflammatory stimuli for dendritic cells (DCs), which in turn activate CD8+ T cells through a process called antigen cross-priming. To define how different forms of programmed cell death influence immunity, we established models of necroptosis and apoptosis, where dying cells are generated by RIPK3 and CASP8 dimerization, respectively. We found that release of inflammatory mediators such as damage-associated molecular patterns (DAMPs) by dying cells was not sufficient for CD8+ T cell cross-priming. Instead, robust cross-priming required RIPK1 signaling and NF-κB-induced transcription within dying cells. Decoupling NF-κB signaling from necroptosis or inflammatory apoptosis reduced priming efficiency and tumor immunity. Our results reveal that coordinated inflammatory and cell death signaling pathways within dying cells orchestrate adaptive immunity.

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

“…In accord with this conclusion, artificial activation of a RIP3 construct that has been rendered susceptible to dimerization by chemical agents can stimulate ICD. 41 In that paper, RIP3 activation by dimerization was shown to lead to the activation of RIP1, which in turn stimulated an NF-kB-mediated transcriptional program that contributed to the immunogenicity of dying cells. 41 Anthracyclines potently induce the NF-kB pathway in a RIP1-dependent fashion, 42,43 suggesting that this pathway may contribute to chemotherapy-elicited ICD as well.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…97 Such a chemokine mixture is particularly efficient at recruiting neutrophils towards the dying cells (a process that appears to be evolutionarily conserved), paving the way to the CALR-dependent phagocytosis of dying cancer cells or corpses thereof, and the cytotoxic targeting of residual malignant cells. 97 We characterized a naturally-occurring preclinical model of cancer that exhibits intrinsic resistance against mitoxantrone-induced ICD in vivo secondary to a defect in CALR exposure, 199 and we documented that anthracyclines and oxaliplatin can trigger a necroptotic variant of ICD [211][212][213][214][215] in cancer cells expressing receptor interacting serine/threonine kinase 3 (RIP3K) and the pseudokinase mixed lineage kinase domain-like (MLKL). 215 Finally, we found that an engineered oncolytic vaccinia virus 216 can induce ICDdependent antitumor immunity, which can be further potentiated by the co-administration of ICD-inducing chemotherapy or immune checkpoint blockers (ICBs), 216 and that pharmacological inhibition of signal transducer and activator of transcription 3 (STAT3) 217 signaling boosts the therapeutic efficacy of anthracyclines upon increased type I interferon (IFN) secretion.…”

Hitting the right button: MAVS-mediated defense against HAV infection

“…The self-limited course of hepatic HAV infection may be determined by this MAVS-dominated hepatocyteintrinsic innate immune defense. Since necroptotic cell death determines immunogenic activation of antigen-presenting dendritic cells for cross-priming of CD8 T cells that are necessary for protective immunity against virus infection [9], more details need to be known on the mode of MAVS/IRF3-induced death in HAV-infected hepatocytes and how this translates into protective immunity against HAV. In HBV infection, no viral immune escape in hepatocytes has been reported, and HBV is rather considered a stealth non-cytopathic virus that evades rather than actively modulates innate immune response [1].…”