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Series GSE202304 Query DataSets for GSE202304
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
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.
Overall design ATAC-seq of PANC1 cell line with shRNA mediated SIK3 knockdown was treated with human TNF or vehicle control
Contributor(s) Sorrentino A, Schmidl C, Nur Menevse A
Citation(s) 35606086
Submission date May 05, 2022
Last update date Jun 27, 2022
Contact name Claudia GEBHARD
ZIP/Postal code 93042
Country Germany
Platforms (1)
GPL21697 NextSeq 550 (Homo sapiens)
Samples (16)
GSM6124068 BW10s1_PANC1_R1_1-Scr-0-24h1
GSM6124069 BW10s17_PANC1_R3_Scr-0-24h
GSM6124070 BW10s18_PANC1_R3_Scr-100-24h
This SubSeries is part of SuperSeries:
GSE202305 RNA-seq and ATAC-seq of tumor resistance to immune cell attack
BioProject PRJNA836530

Download family Format
SOFT formatted family file(s) SOFTHelp
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Supplementary file Size Download File type/resource
GSE202304_RAW.tar 7.3 Gb (http)(custom) TAR (of BED, BIGWIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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