{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:56:03Z","timestamp":1790787363153,"version":"4.1.0"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005601","name":"CLL Global Research Foundation","doi-asserted-by":"publisher","award":["AWD-115284"],"award-info":[{"award-number":["AWD-115284"]}],"id":[{"id":"10.13039\/100005601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005601","name":"CLL Global Research Foundation","doi-asserted-by":"publisher","award":["AWD-116510"],"award-info":[{"award-number":["AWD-116510"]}],"id":[{"id":"10.13039\/100005601","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,12]]},"abstract":"<jats:p>\n                    Poorly differentiated gastric carcinomas (PDGC) comprise 30% of gastric cancers and are associated with poor prognosis, correlating with tumor size and microvascular invasion. PDGC may be subcategorized as Epstein\u2013Barr virus (EBV)-positive or EBV-negative. Based on prior work with EBV-positive nasopharyngeal carcinomas, we interrogated 33 PDGC samples for EBV DNA\/RNA\/protein, CD8, PDL1, PD1, Inducible T cell Co-Stimulator Ligand (ICOSL), ICOS, MHC-I, Suppressor of cytokine signaling 1 (SOCS1), and\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    . The 13 EBV-positive tumors each showed intense PD1, PDL1, and CD8+ T cell responses that were largely absent in EBV-negative tumors. EBV EBER-1\/2 RNA strongly colocalized with\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    in cancer cells with a concomitant loss of ICOSL expression as well as downregulation of cytokine signaling suppressor, SOCS1. In contrast, the 20 EBV-negative PDGCs showed weak to no\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    expression, with strong ICOSL and SOCS1 expression. On the other hand, the MHC-I expression was lost in both PDGC types. These data suggest that, despite the similar histological patterns of the cancer cells, EBV-driven induction of\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    suppresses SOCS1 expression, resulting in intense cytotoxic T cell infiltration, but also loss of the other\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    target, ICOSL, making tumor cells invisible to the surrounding intense T cell infiltration. Conversely, EBV-negative tumors retain ICOSL\/SOCS1 expression, but exhibit minimal T cell infiltration, partly due to high SOCS1 expression, preventing immune-mediated clearance. Overall, our data indicate that SOCS1 expression, regulated by EBV-induced\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    , along with ICOSL status determines whether tumors attract T cells and whether those T cells can effectively eradicate cancer cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2536375123","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T09:47:13Z","timestamp":1778579233000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["<i>MiR-155<\/i>\n                    -driven loss of ICOSL and SOCS1 in EBV+ gastric cancers renders abundant cytotoxic T cells ineffective, enabling immune evasion"],"prefix":"10.1073","volume":"123","author":[{"given":"Gerard J.","family":"Nuovo","sequence":"first","affiliation":[{"name":"GNOME Diagnostics","place":["Powell"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3897-9974","authenticated-orcid":false,"given":"Koshi","family":"Mimori","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyushu University Beppu Hospital","place":["Beppu, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Otsu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyushu University Beppu Hospital","place":["Beppu, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmerina","family":"Tili","sequence":"additional","affiliation":[{"name":"The Ohio State University, Comprehensive Cancer Center and The Ohio State University College of Medicine, Wexner Medical Center, Department of Cancer Biology and Genetics","place":["Columbus"]},{"id":[{"id":"https:\/\/ror.org\/00rs6vg23","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, The Ohio State University, and The Ohio State University College of Medicine, Wexner Medical Center","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3788-1457","authenticated-orcid":false,"given":"Carlo M.","family":"Croce","sequence":"additional","affiliation":[{"name":"The Ohio State University, Comprehensive Cancer Center and The Ohio State University College of Medicine, Wexner Medical Center, Department of Cancer Biology and Genetics","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0029-1214758"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.583463"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.006"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.05.010"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.11.009"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25501"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.25459"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0768-9"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1080\/00365521.2023.2286194"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2024.102737"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0211358"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000316"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2021.1938381"},{"key":"e_1_3_4_14_2","first-page":"5006","article-title":"PD-1 antibody camrelizumab for Epstein-Barr virus-positive metastatic gastric cancer: A single-arm, open-label, phase 2 trial","volume":"11","author":"Sun Y. 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