{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T07:18:59Z","timestamp":1771917539240,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,1,24]],"date-time":"2021-01-24T00:00:00Z","timestamp":1611446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Thoracic Cancer"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Immune checkpoint inhibitors targeting the programmed cell death\u20101 (PD\u20101)\/PD\u20101 ligand 1 (PD\u2010L1) axis have shown promising results in patients with nonsmall cell lung cancer (NSCLC). One major PD\u2010L1 inducer is IFN\u03b3, which is secreted by T cells and NK cells. Importantly, IFN\u03b3\u2010induced PD\u2010L1 is one of the major mechanisms by which cancer cells escape host immunity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we found that the NSCLC cell line, LC\u20102\/ad, has a unique character; the PD\u2010L1 expression in these cells is up\u2010regulated by both IFN\u03b3 and epidermal growth factor (EGF).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Comparative analysis of the cell signaling pathway showed that IFN\u03b3 activates STAT1 signaling, while EGF activates AKT, MAPK, and ribosomal protein S6 kinase in LC\u20102\/ad cells. IFN\u03b3\u2010induced PD\u2010L1, but not EGF\u2010induced PD\u2010L1, was clearly blocked by the JAK\u2010STAT inhibitor tofacitinib. Interestingly, IFN\u03b3 decreased the expression of NK cell\u2010activating ligands while increasing the expression of MHC class I molecules, resulting in a phenotype that can easily escape from NK cells, theoretically. Finally, we showed that IFN\u03b3 stimuli attenuated NK cell\u2010mediated cytotoxicity in LC\u20102\/ad cells, which was, however, blocked by tofacitinib.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Taken together, our study shows that tofacitinib blocks the IFN\u03b3\u2010induced transformation from an NK cell\u2010sensitive phenotype to an NK cell\u2010resistant one in IFN\u03b3\u2010reacted LC\u20102\/ad cells, thereby implicating that tofacitinib may be a promising agent to overcome IFN\u03b3\u2010induced tumor immune escape, although it may be adapted to the limited number of NSCLC patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1759-7714.13847","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T06:31:55Z","timestamp":1611556315000},"page":"775-782","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Tofacitinib overcomes an <scp>IFN\u03b3<\/scp>\u2010induced decrease in <scp>NK<\/scp> cell\u2010mediated cytotoxicity via the regulation of immune\u2010related molecules in <scp>LC<\/scp>\u20102\/ad"],"prefix":"10.1111","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1343-1275","authenticated-orcid":false,"given":"Riki","family":"Okita","sequence":"first","affiliation":[{"name":"Department of General Thoracic Surgery Kawasaki Medical School  Kurashiki Japan"},{"name":"Division of Thoracic Surgery National Hospital Organization Yamaguchi Ube Medical Center  Ube Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuhiko","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery Kawasaki Medical School  Kurashiki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Nojima","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery Kawasaki Medical School  Kurashiki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinsuke","family":"Saisho","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery Kawasaki Medical School  Kurashiki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masao","family":"Nakata","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery Kawasaki Medical School  Kurashiki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,1,24]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.20006"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1507643"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504627"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910231"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.09.006"},{"issue":"6","key":"e_1_2_11_7_1","first-page":"607","article-title":"Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period","volume":"1","author":"Lister J","year":"1995","journal-title":"Clin Cancer Res"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.5449"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm730"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139809"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102237"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.12768"},{"issue":"2","key":"e_1_2_11_13_1","first-page":"839","article-title":"Effect of platinumbased chemotherapy on the expression of natural killer group 2 member D ligands, programmed cell death1 ligand 1 and HLA class I in nonsmall cell lung cancer","volume":"42","author":"Okita R","year":"2019","journal-title":"Oncol Rep"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.12.093"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-017-1986-y"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0331"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.7.3948"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-3283"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/319675a0"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.172.6.1589"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.2.905"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109071"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-09-305425"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0310"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu242"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0215(19980911)77:6<937::AID-IJC24>3.0.CO;2-X"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03884"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007579"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2008.00791.x"}],"container-title":["Thoracic Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1759-7714.13847","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/1759-7714.13847","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1759-7714.13847","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T15:08:01Z","timestamp":1693580881000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/1759-7714.13847"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,24]]},"references-count":28,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["10.1111\/1759-7714.13847"],"URL":"https:\/\/doi.org\/10.1111\/1759-7714.13847","archive":["Portico"],"relation":{},"ISSN":["1759-7706","1759-7714"],"issn-type":[{"value":"1759-7706","type":"print"},{"value":"1759-7714","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,24]]},"assertion":[{"value":"2020-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}