{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T01:33:22Z","timestamp":1788140002247,"version":"build-2803163510"},"reference-count":31,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"unspecified","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Takeda, NIH","award":["R01CA262377"],"award-info":[{"award-number":["R01CA262377"]}]},{"name":"Takeda, NIH","award":["R03CA219603"],"award-info":[{"award-number":["R03CA219603"]}]},{"name":"Takeda, NIH","award":["R37CA245154"],"award-info":[{"award-number":["R37CA245154"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,7,1]]},"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The expression of SYK in cancer cells has been associated with both tumor promoting and tumor suppressive effects. Despite being proposed as anticancer therapeutic target, the possible role of SYK in modulating local adaptive antitumor immune responses remains uncertain. Using detailed analysis of primary human tumors and in vitro models, we reveal the immunomodulatory effect of SYK protein in human solid cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We spatially mapped SYK kinase in tumor cells, stromal cells and tumor-infiltrating leukocytes (TILs) in 808 primary non-small cell lung carcinomas (NSCLCs) from two cohorts and in 374 breast carcinomas (BCs) from two independent cohorts. We established the associations of localized SYK with clinicopathologic variables and outcomes. The immunomodulatory role of SYK on tumor cells was assessed using in vitro cytokine stimulation, transcriptomic analysis and selective SYK blockade using a small molecule inhibitor. Functional responses were assessed using cocultures of tumor cells with peripheral blood lymphocytes. T cell responses in baseline and post-treatment biopsies from patients with BC treated with a SYK inhibitor in a phase I clinical trial were also studied.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Elevated tumor cell or leukocyte SYK expression was associated with high CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> TILs and better outcome in both NSCLC and BC. Tumor cell SYK was associated with oncogenic driver mutations in EGFR or KRAS in lung adenocarcinomas and with triple negative phenotype in BC. In cultured tumor cells, SYK was upregulated by TNF\u03b1 and required for the TNF\u03b1-induced proinflammatory responses and T cell activation. SYK blockade after nivolumab in a phase I clinical trial including three patients with advanced triple negative BC reduced TILs and T cell proliferation. Our work establishes the proinflammatory function of tumor cell SYK in lung and breast cancer. SYK signaling in cultured tumor cells is required for T cell activation and SYK blockade limits adaptive antitumor immune responses and tumor rejection in patients with cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Together, our results establish the immunomodulatory role of SYK expression in human solid tumors. This information could be used to develop novel biomarkers and\/or therapeutic strategies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-005113","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T11:27:40Z","timestamp":1658489260000},"page":"e005113","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Tumor cell SYK expression modulates the tumor immune microenvironment composition in human cancer via TNF-\u03b1 dependent signaling"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"nct02834247","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02834247","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02834247","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02834247","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Adam","family":"Aguirre-Ducler","sequence":"first","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA"},{"name":"Translational Medicine Laboratory, Department of Cancer Research, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 8320000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Gianino","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0080-2444","authenticated-orcid":false,"given":"Franz","family":"Villarroel-Espindola","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5234-5890","authenticated-orcid":false,"given":"Shruti","family":"Desai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiwei","family":"Tang","sequence":"additional","affiliation":[{"name":"Yale School of Public Health, Yale University, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Yale School of Public Health, Yale University, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Syrigos","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Athens, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William L","family":"Trepicchio","sequence":"additional","affiliation":[{"name":"Takeda Oncology, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karuppiah","family":"Kannan","sequence":"additional","affiliation":[{"name":"Takeda Oncology, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C","family":"Gregory","sequence":"additional","affiliation":[{"name":"Takeda Oncology, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5692-4833","authenticated-orcid":false,"given":"Kurt A","family":"Schalper","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"2025100314204933000_10.7.e005113.1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1056"},{"key":"2025100314204933000_10.7.e005113.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2005.11.004"},{"key":"2025100314204933000_10.7.e005113.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009048107"},{"key":"2025100314204933000_10.7.e005113.4","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5788"},{"key":"2025100314204933000_10.7.e005113.5","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.bbamcr.2014.10.022","article-title":"Calling in SYK: SYK\u2019s dual role as a tumor promoter and tumor suppressor in cancer","volume":"1853","author":"Krisenko","year":"2015","journal-title":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"2025100314204933000_10.7.e005113.6","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2040"},{"key":"2025100314204933000_10.7.e005113.7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-2104"},{"key":"2025100314204933000_10.7.e005113.8","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004088"},{"key":"2025100314204933000_10.7.e005113.9","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3239"},{"key":"2025100314204933000_10.7.e005113.10","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2690"},{"key":"2025100314204933000_10.7.e005113.11","doi-asserted-by":"publisher","DOI":"10.1038\/35021086"},{"key":"2025100314204933000_10.7.e005113.12","first-page":"582","article-title":"Linking inflammation and cancer: the unexpected SYK world","volume":"20","author":"Fueyo","year":"2018","journal-title":"Neuro Oncol"},{"key":"2025100314204933000_10.7.e005113.13","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1093\/neuonc\/noy008","article-title":"SYK inhibition blocks proliferation and migration of glioma cells and modifies the tumor microenvironment","volume":"20","author":"Moncayo","year":"2018","journal-title":"Neuro Oncol"},{"key":"2025100314204933000_10.7.e005113.14","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-19-0947"},{"key":"2025100314204933000_10.7.e005113.15","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2542"},{"key":"2025100314204933000_10.7.e005113.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0339-5"},{"key":"2025100314204933000_10.7.e005113.17","doi-asserted-by":"crossref","DOI":"10.1093\/jnci\/dju435","article-title":"Objective measurement and clinical significance of TILs in non-small cell lung cancer","volume":"107","author":"Schalper","year":"2015","journal-title":"J Natl Cancer Inst"},{"key":"2025100314204933000_10.7.e005113.18","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3344"},{"key":"2025100314204933000_10.7.e005113.19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700893"},{"key":"2025100314204933000_10.7.e005113.20","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-4142"},{"key":"2025100314204933000_10.7.e005113.21","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3995"},{"key":"2025100314204933000_10.7.e005113.22","doi-asserted-by":"crossref","first-page":"161","DOI":"10.12688\/f1000research.10851.1","article-title":"The challenges with the validation of research antibodies","volume":"6","author":"Voskuil","year":"2017","journal-title":"F1000Res"},{"key":"2025100314204933000_10.7.e005113.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2016.10.087"},{"key":"2025100314204933000_10.7.e005113.24","doi-asserted-by":"crossref","first-page":"25575","DOI":"10.18632\/oncotarget.4669","article-title":"Increased Syk activity is associated with unfavorable outcome among patients with acute myeloid leukemia","volume":"6","author":"Boros","year":"2015","journal-title":"Oncotarget"},{"key":"2025100314204933000_10.7.e005113.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3835(02)00463-9"},{"key":"2025100314204933000_10.7.e005113.26","first-page":"547","article-title":"Promoter hypermethylation of the 14-3-3 sigma, Syk and CAGE-1 genes is related to the various phenotypes of urinary bladder carcinomas and associated with progression of transitional cell carcinomas","volume":"18","author":"Kunze","year":"2006","journal-title":"Int J Mol Med"},{"key":"2025100314204933000_10.7.e005113.27","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.090543"},{"key":"2025100314204933000_10.7.e005113.28","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0266"},{"key":"2025100314204933000_10.7.e005113.29","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1038\/labinvest.2014.118","article-title":"Downregulation of spleen tyrosine kinase in hepatocellular carcinoma by promoter CpG island hypermethylation and its potential role in carcinogenesis","volume":"94","author":"Shin","year":"2014","journal-title":"Lab Invest"},{"key":"2025100314204933000_10.7.e005113.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.03.022"},{"key":"2025100314204933000_10.7.e005113.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05032-8"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2022-005113","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T21:20:57Z","timestamp":1759526457000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2022-005113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7]]},"references-count":31,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7,22]]},"published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1136\/jitc-2022-005113"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2022-005113","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7]]}}}