Salt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
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 (TC) 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 TC-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with tumor-infiltrating lymphocytes and antigen-specific TCs.
RESULTS: The 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.
CONCLUSION: Our data reveal an abundant molecular mechanism that protects tumor cells from cytotoxic TC attack and demonstrate that pharmacological inhibition of this pathway is feasible.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 10(2022), 5 vom: 23. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sorrentino, Antonio [VerfasserIn] |
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| Links: |
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| Themen: |
CD8-positive T-lymphocytes |
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| Anmerkungen: |
Date Completed 25.05.2022 Date Revised 16.07.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2021-004258 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Sorrentino, Antonio |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Salt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 25.05.2022 | ||
| 500 | |a Date Revised 16.07.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a 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 (TC) attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies | ||
| 520 | |a METHODS: To 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 | ||
| 520 | |a RESULTS: The 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 | ||
| 520 | |a CONCLUSION: Our data reveal an abundant molecular mechanism that protects tumor cells from cytotoxic TC attack and demonstrate that pharmacological inhibition of this pathway is feasible | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CD8-positive T-lymphocytes | |
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| 700 | 1 | |a Michels, Tillmann |e verfasserin |4 aut | |
| 700 | 1 | |a Volpin, Valentina |e verfasserin |4 aut | |
| 700 | 1 | |a Durst, Franziska Christine |e verfasserin |4 aut | |
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| 700 | 1 | |a Stamova, Slava |e verfasserin |4 aut | |
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| 700 | 1 | |a Muehlbauer, Jasmin |e verfasserin |4 aut | |
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| 700 | 1 | |a Rathinasamy, Anchana |e verfasserin |4 aut | |
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| 700 | 1 | |a Breinig, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Mikietyn, Damian |e verfasserin |4 aut | |
| 700 | 1 | |a Kohler, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Poschke, Isabel |e verfasserin |4 aut | |
| 700 | 1 | |a Purr, Sabrina |e verfasserin |4 aut | |
| 700 | 1 | |a Reidell, Olivia |e verfasserin |4 aut | |
| 700 | 1 | |a Martins Freire, Catarina |e verfasserin |4 aut | |
| 700 | 1 | |a Offringa, Rienk |e verfasserin |4 aut | |
| 700 | 1 | |a Gebhard, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Spang, Rainer |e verfasserin |4 aut | |
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