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Status |
Public on Jun 06, 2022 |
Title |
Salt-inducible kinase 3 protects tumor cells from cytotoxic T cell attack by promoting TNF-induced NF-κB activation |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Background: Cancer 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 attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies. Methods: To identify novel genes that protect tumor cells from effective T cell-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with TILs and antigen-specific T cells. Results: The screening revealed 108 potential genes that protected tumor cells from T cell attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibition of SIK3 in tumor cells dramatically increased T cell-mediated cytotoxicity in several in vitro co-culture models, using different sources of tumor and T cells. Consistently, adoptive T cell 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 TNF secreted by tumor-activated T cells. SIK3 promoted NF-ΚB nuclear translocation and inhibited Caspase-8 and -9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of pro-survival genes under the TNF-NF-ΚB axis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase (IKK) and NF-kappa-B inhibitor alpha (IκBα) on the one side, and to inhibition of histone deacetylase 4 (HDAC4) 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 T cell activity and poor prognosis.
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Overall design |
ATAC-seq of PANC1 cell line with shRNA mediated SIK3 knockdown was treated with human TNF or vehicle control
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Contributor(s) |
Sorrentino A, Schmidl C, Nur Menevse A |
Citation(s) |
35606086 |
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Submission date |
May 05, 2022 |
Last update date |
Jun 27, 2022 |
Contact name |
Claudia GEBHARD |
E-mail(s) |
claudia.gebhard@gmail.com
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Organization name |
UNIVERSITY HOSPITAL REGENSBURG
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Street address |
FRANZ-JOSEF-STRAUSS ALLEE 11
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City |
REGENSBURG |
ZIP/Postal code |
93042 |
Country |
Germany |
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Platforms (1) |
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Samples (16)
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This SubSeries is part of SuperSeries: |
GSE202305 |
RNA-seq and ATAC-seq of tumor resistance to immune cell attack |
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Relations |
BioProject |
PRJNA836530 |