Abstract
BackgroundNecroptosis is emerging as a new target for cancer immunotherapy as it is now recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis appears especially important in facilitating increased anti-tumor immune responses. While late-stage transcription mediated by NF-κB during cell death is believed to play a role in this process, it is otherwise unclear what cell signaling events initiate this transactivation of inflammatory genes.MethodsWe employed tandem-affinity purification linked to mass spectrometry (TAP-MS), in combination with the analysis of RNA-sequencing (RNA-Seq) datasets to identify the Tripartite Motif Protein 28 (TRIM28) as a candidate co-repressor. Comprehensive biochemical and molecular biology techniques were used to characterize the role of TRIM28 in RIPK3 activation-induced transcriptional and immunomodulatory events. The cell composition estimation module was used to evaluate the correlation between RIPK3/TRIM28 levels and CD8+ T cells or dendritic cells (DC) in all TCGA tumors.ResultsWe identified TRIM28 as a co-repressor that regulates transcriptional activity during necroptosis. Activated RIPK3 phosphorylates TRIM28 on serine 473, inhibiting its chromatin binding activity, thereby contributing to the transactivation of NF-κB and other transcription factors, such as SOX9. This leads to elevated cytokine expression, which then potentiates immunoregulatory processes, such as DC maturation. The expression of RIPK3 has a significant positive association with the tumor-infiltrating immune cells populations in various tumor type, thereby activating anti-cancer responses.ConclusionOur data suggest that RIPK3 activation-dependent derepression of TRIM28 in cancer cells leads to increased immunostimulatory cytokine production in the tumor microenvironment, which then contributes to robust cytotoxic anti-tumor immunity.
Highlights
Necroptosis is emerging as a new target for cancer immunotherapy as it is recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transactivation alone is insufficient to explain necroptosis-specific cytokine production It has been reported that the RIPK1/Receptor-interacting protein kinases 3 (RIPK3) necrosome complex activation triggers cytokine gene transcription through a cell-autonomous mechanism involving NF-κB; this is proposed to occur independently of damageassociated molecular patterns (DAMP) release by the dying cells [9]
While NF-κB is reported to be critical for cytokine transcription in this case, it remains unknown if NF-κB transactivation is sufficient to trigger necroptosis-mediated transcriptional activation on its own
Summary
Necroptosis is emerging as a new target for cancer immunotherapy as it is recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis appears especially important in facilitating increased anti-tumor immune responses. Necroptosis is a form of regulated necrotic cell death; its essential molecular machinery consist of two receptor-interacting protein kinases (RIPK1 and RIPK3), and mixed lineage kinase domain-like pseudokinase (MLKL) [3]. Necroptotic cells may play multiple roles in innate immunity and shape the subsequent adaptive immunity through the release of endogenous danger signals known as damage-associated molecular patterns (DAMPs) [6, 7]. The activation of RIPK1/RIPK3 leads to the upregulation of inflammatory chemokines that promote the cross-priming of CD8+ T cell vaccination responses [11,12,13]; the presence of intratumoral chemokines is positively correlated with cytotoxic CD8+ T cell (CTL) infiltration [14] indicating that the activation of necroptosis signaling provides anti-tumor immunity
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