ArticleJournal for immunotherapy of cancer2022
Salt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation.
Article in Journal for immunotherapy of cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 19 citations in OpenAlex.
- Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a phase I/II open-label multicenter study.Haematologica · 2024Trial
- B-cell lymphocytosis and reprogramming due to biallelic CARD11 mutations.The Journal of allergy and clinical immunology · 2026Article
- Advanced Human Immune Cell-Organoid Co-Cultures for Functional Testing of Cancer Nanovaccines.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Clustering of Omic Data Using Semi-Supervised Transfer Learning for Gaussian Mixture Models via Natural-Gradient Variational Inference: Method and Applications to Bulk and Single-Cell Transcriptomics.bioRxiv : the preprint server for biology · 2025Article
- Inflammation, microbiota, and pancreatic cancer.Cancer cell international · 2025Review
- EFHD1 Activates SIK3 to Limit Colorectal Cancer Initiation and Progression via the Hippo Pathway.Journal of Cancer · 2025Article
- Mechanistic insights into resistance mechanisms to T cell engagers.Frontiers in immunology · 2025Review
- Cellular heterogeneity in TNF/TNFR1 signalling: live cell imaging of cell fate decisions in single cells.Cell death & disease · 2024Review
- Article
- TP53 to mediate immune escape in tumor microenvironment: an overview of the research progress.Molecular biology reports · 2024Review
- Roles of salt‑inducible kinases in cancer (Review).International journal of oncology · 2023Review
- Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas.Acta neuropathologica · 2023Article
- The multiple roles of salt-inducible kinases in regulating physiology.Physiological reviews · 2023Review
- TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma.Acta neuropathologica communications · 2023Article
Corrections and comments
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Authors and funding
30 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCancer immunotherapeutic strategies showed unprecedented results in the clinic. However, many patients do not respond to immuno-oncological treatments due to the occurrence of a plethora of immunological obstacles, including tumor intrinsic mechanisms of resistance to cytotoxic T-cell (TC) attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies.
methodsTo identify novel genes that protect tumor cells from effective TC-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with tumor-infiltrating lymphocytes and antigen-specific TCs.
resultsThe screening revealed 108 potential genes that protected tumor cells from TC attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibitions of SIK3 in tumor cells dramatically increased TC-mediated cytotoxicity in several in vitro coculture models, using different sources of tumor and TCs. Consistently, adoptive TC transfer of TILs led to tumor growth inhibition of SIK3-depleted cancer cells in vivo. Mechanistic analysis revealed that SIK3 rendered tumor cells susceptible to tumor necrosis factor (TNF) secreted by tumor-activated TCs. SIK3 promoted nuclear factor kappa B (NF-κB) nuclear translocation and inhibited caspase-8 and caspase-9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of prosurvival genes under the TNF-NF-κB axis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase and NF-kappa-B inhibitor alpha on the one side, and to inhibition of histone deacetylase 4 on the other side, thus sustaining NF-κB activation and nuclear stabilization. A SIK3-dependent gene signature of TNF-mediated NF-κB activation was found in a majority of pancreatic cancers where it correlated with increased cytotoxic TC activity and poor prognosis.
conclusionOur data reveal an abundant molecular mechanism that protects tumor cells from cytotoxic TC attack and demonstrate that pharmacological inhibition of this pathway is feasible.
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