RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment

Abstract

Background Necroptosis 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. Methods We 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. Results We 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. Conclusion Our 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.

Regulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections

“…Regulated necrosis can be blocked and induced in some diseases, like cancers. It is well known that cancer cells exhibit resistance to cell apoptosis, necroptosis, and ferroptosis, showing promising performance in eliminating certain kinds of therapy-resistant cancer cells [ 80 , 82 , 83 ].…”

“…Moreover, in testing with various tumor types, RIPK3 activation can induce the expression of immunostimulatory cytokines, leading to an increased antitumor immunity [ 83 ]. Data showed that loss of GPX4 function either by genetic inactivation or pharmacological treatment could induce selective ferroptosis in cancer cells in vitro and also guard against tumor recrudesce in mice [ 84 , 85 ], indicating that rationally manipulating ferroptosis or necroptosis or both may be an attractive way to treat certain kinds of cancers in clinic.…”

Immunotherapy landscape analyses of necroptosis characteristics for breast cancer patients

“…Parkin could promote the polyubiquitination of RIPK3, and parkin overexpression was associated with worse prognosis in BC patients [8]. Moreover, Park et al also showed that the activation of necroptosis inhibited tripartite motif protein 28 (TRIM28) and then increased the production of immunostimulatory cytokine, which resulted in enhanced anti-tumor immunity [9]. These studies suggest that necroptosis-related genes (NRGs) are valuable predictors of prognosis and the efficacy of immunotherapy for BC patients, as well as promising treatment targets.…”

Pathogenesis of Choledochal Cyst: Insights from Genomics and Transcriptomics

“…PPI pair TRIM28 and ZNF382 were overrepresented in CC group compared to controls in PPI analyses, with 3 and 2 patients carrying rare damaging variants on these two genes, respectively. TRIM28, known for regulation of the endoderm differentiation and involvement in malignancy, may play a role in CC [ 71 , 72 , 73 , 74 ]. Though the whole exome sequencing study was limited by a small sample size, CC is regarded as a multigenetic disease with mutations in more than one gene with genetic heterogeneity [ 56 ].…”