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000180022 1001_ $$0P:(DE-He78)3b7da5ed0bbbfa153e8bdf23d212ae8c$$aSorrentino, Antonio$$b0$$eFirst author
000180022 245__ $$aSalt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation.
000180022 260__ $$aLondon$$bBioMed Central$$c2022
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000180022 520__ $$aCancer 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.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.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.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.
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000180022 650_7 $$2Other$$aCD8-positive T-lymphocytes
000180022 650_7 $$2Other$$acytokines
000180022 650_7 $$2Other$$aimmunomodulation
000180022 650_7 $$2Other$$aimmunotherapy
000180022 650_7 $$2Other$$atumor escape
000180022 7001_ $$aMenevse, Ayse Nur$$b1
000180022 7001_ $$0P:(DE-He78)9ddf8548567817f5761b4db4cca412d3$$aMichels, Tillmann$$b2
000180022 7001_ $$0P:(DE-He78)b047f9932dd30887b942fa53c39d415e$$aVolpin, Valentina$$b3
000180022 7001_ $$00000-0001-6714-0321$$aDurst, Franziska Christine$$b4
000180022 7001_ $$aSax, Julian$$b5
000180022 7001_ $$aXydia, Maria$$b6
000180022 7001_ $$aHussein, Abir$$b7
000180022 7001_ $$aStamova, Slava$$b8
000180022 7001_ $$aSpoerl, Steffen$$b9
000180022 7001_ $$aHeuschneider, Nicole$$b10
000180022 7001_ $$aMuehlbauer, Jasmin$$b11
000180022 7001_ $$aJeltsch, Katharina Marlene$$b12
000180022 7001_ $$aRathinasamy, Anchana$$b13
000180022 7001_ $$aWerner-Klein, Melanie$$b14
000180022 7001_ $$0P:(DE-He78)a7f6241ee41dbfd09892f8027db893d0$$aBreinig, Marco$$b15$$udkfz
000180022 7001_ $$aMikietyn, Damian$$b16
000180022 7001_ $$aKohler, Christian$$b17
000180022 7001_ $$0P:(DE-He78)e9c55f46b4b06cf835834ee7e3e00db8$$aPoschke, Isabel$$b18$$udkfz
000180022 7001_ $$0P:(DE-HGF)0$$aPurr, Sabrina$$b19
000180022 7001_ $$aReidell, Olivia$$b20
000180022 7001_ $$aMartins Freire, Catarina$$b21
000180022 7001_ $$0P:(DE-He78)81ae96953d6149e4307057d71a190019$$aOffringa, Rienk$$b22$$udkfz
000180022 7001_ $$aGebhard, Claudia$$b23
000180022 7001_ $$aSpang, Rainer$$b24
000180022 7001_ $$aRehli, Michael$$b25
000180022 7001_ $$0P:(DE-He78)3c0da8e3caa2aa50cad85152aa0465ad$$aBoutros, Michael$$b26$$udkfz
000180022 7001_ $$aSchmidl, Christian$$b27
000180022 7001_ $$0P:(DE-He78)28a758c72be594bcb254fe9f3ac6be04$$aKhandelwal, Nisit$$b28
000180022 7001_ $$0P:(DE-He78)1732377f6242a18280bc6aaa196988d1$$aBeckhove, Philipp$$b29$$eLast author
000180022 773__ $$0PERI:(DE-600)2719863-7$$a10.1136/jitc-2021-004258$$gVol. 10, no. 5, p. e004258 -$$n5$$pe004258$$tJournal for ImmunoTherapy of Cancer$$v10$$x2051-1426$$y2022
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