{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:38:29Z","timestamp":1787017109984,"version":"build-2736575974"},"reference-count":50,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"unspecified","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005426","name":"Etel\u00e4-Savon Rahasto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007797","name":"Helsingin Yliopisto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007797","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004012","name":"Jane ja Aatos Erkon S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004012","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HUCH Research Funds"},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008723","name":"Suomen L\u00e4\u00e4ketieteen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008723","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004212","name":"P\u00e4ivikki ja Sakari Sohlbergin S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004212","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009067","name":"K. Albin Johanssons Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009067","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006383","name":"Sy\u00f6p\u00e4j\u00e4rjest\u00f6t","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006383","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Open access funded by Helsinki University Library"},{"name":"Finnish-Norwegian Medical Foundation"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5\/3\u220624-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"isrctn\" xlink:href=\"10141600\">ISRCTN10141600<\/jats:ext-link>\n                      , April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging\/marker responses were evaluated by log-rank and Fisher\u2019s test, while coinhibitory receptors\/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Preclinically, TIM-3\n                      <jats:sup>+<\/jats:sup>\n                      tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3\n                      <jats:sup>+<\/jats:sup>\n                      TIL subset through recruitment of less-exhausted CD8\n                      <jats:sup>+<\/jats:sup>\n                      TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8\n                      <jats:sup>+<\/jats:sup>\n                      lymphocytes and higher influx of CD8\n                      <jats:sup>+<\/jats:sup>\n                      TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2021-003490","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T11:25:55Z","timestamp":1645529155000},"page":"e003490","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Oncolytic adenovirus decreases the proportion of TIM-3\n                    <sup>+<\/sup>\n                    subset of tumor-infiltrating CD8\n                    <sup>+<\/sup>\n                    T cells with correlation to improved survival in patients with cancer"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"isrctn10141600","registry":"10.18810\/isrctn"},{"clinical-trial-number":"isrctn10141600","registry":"10.18810\/isrctn"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0669-3587","authenticated-orcid":false,"given":"Ilkka","family":"Liikanen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saru","family":"Basnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafne C A","family":"Quixabeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Taipale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otto","family":"Hemminki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"Oksanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matti","family":"Kankainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juuso","family":"Juhila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kanerva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Joensuu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siri","family":"T\u00e4htinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7103-8530","authenticated-orcid":false,"given":"Akseli","family":"Hemminki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"2022022208251488000_10.2.e003490.1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.58.3377"},{"key":"2022022208251488000_10.2.e003490.2","first-page":"1666","article-title":"[Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus]","volume":"23","author":"Xia","year":"2004","journal-title":"Ai Zheng"},{"key":"2022022208251488000_10.2.e003490.3","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2019.1595582"},{"key":"2022022208251488000_10.2.e003490.4","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-019-00367-0"},{"key":"2022022208251488000_10.2.e003490.5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2546"},{"key":"2022022208251488000_10.2.e003490.6","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-3001"},{"key":"2022022208251488000_10.2.e003490.7","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001621"},{"key":"2022022208251488000_10.2.e003490.8","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-016-0121-5"},{"key":"2022022208251488000_10.2.e003490.9","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055318"},{"key":"2022022208251488000_10.2.e003490.10","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/s41577-019-0224-6","article-title":"TIM3 comes of age as an inhibitory receptor","volume":"20","author":"Wolf","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"2022022208251488000_10.2.e003490.11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100637"},{"key":"2022022208251488000_10.2.e003490.12","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2021.579351","article-title":"TIM-3 as a prognostic marker and a potential immunotherapy target in human malignant tumors: a meta-analysis and bioinformatics validation","volume":"11","author":"Zang","year":"2021","journal-title":"Front Oncol"},{"key":"2022022208251488000_10.2.e003490.13","doi-asserted-by":"crossref","DOI":"10.4161\/2162402X.2014.989771","article-title":"Serum HMGB1 is a predictive and prognostic biomarker for oncolytic immunotherapy","volume":"4","author":"Liikanen","year":"2015","journal-title":"Oncoimmunology"},{"key":"2022022208251488000_10.2.e003490.14","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/mt.2015.143","article-title":"Chronic activation of innate immunity correlates with poor prognosis in cancer patients treated with oncolytic adenovirus","volume":"24","author":"Taipale","year":"2016","journal-title":"Mol Ther"},{"key":"2022022208251488000_10.2.e003490.15","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000122"},{"key":"2022022208251488000_10.2.e003490.16","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-2908"},{"key":"2022022208251488000_10.2.e003490.17","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41417-020-0189-4","article-title":"Oncolytic virus promotes tumor-reactive infiltrating lymphocytes for adoptive cell therapy","volume":"28","author":"Feist","year":"2021","journal-title":"Cancer Gene Ther"},{"key":"2022022208251488000_10.2.e003490.18","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.26216"},{"key":"2022022208251488000_10.2.e003490.19","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.115"},{"key":"2022022208251488000_10.2.e003490.20","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.18632\/oncotarget.2901","article-title":"Immunological data from cancer patients treated with Ad5\/3-E2F-Delta24-GMCSF suggests utility for tumor immunotherapy","volume":"6","author":"Hemminki","year":"2015","journal-title":"Oncotarget"},{"key":"2022022208251488000_10.2.e003490.21","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.51"},{"key":"2022022208251488000_10.2.e003490.22","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2013.123"},{"key":"2022022208251488000_10.2.e003490.23","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/mt.2015.17","article-title":"T-cell subsets in peripheral blood and tumors of patients treated with oncolytic adenoviruses","volume":"23","author":"Taipale","year":"2015","journal-title":"Mol Ther"},{"key":"2022022208251488000_10.2.e003490.24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302663"},{"key":"2022022208251488000_10.2.e003490.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.04.026"},{"key":"2022022208251488000_10.2.e003490.26","article-title":"Use of mass cytometry to profile human T cell exhaustion","volume":"10","author":"Winkler","year":"2019","journal-title":"Front Immunol"},{"key":"2022022208251488000_10.2.e003490.27","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1038\/s41375-019-0397-9","article-title":"S100A9-induced overexpression of PD-1\/PD-L1 contributes to ineffective hematopoiesis in myelodysplastic syndromes","volume":"33","author":"Cheng","year":"2019","journal-title":"Leukemia"},{"key":"2022022208251488000_10.2.e003490.28","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.immuni.2019.12.006","article-title":"Signaling through the inhibitory Fc receptor Fc\u03b3RIIB induces CD8+ T cell apoptosis to limit T cell immunity","volume":"52","author":"Morris","year":"2020","journal-title":"Immunity"},{"key":"2022022208251488000_10.2.e003490.29","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dju436"},{"key":"2022022208251488000_10.2.e003490.30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41417-021-00303-x","article-title":"Key chemokines direct migration of immune cells in solid tumors","volume":"29","author":"Kohli","year":"2022","journal-title":"Cancer Gene Ther"},{"key":"2022022208251488000_10.2.e003490.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.12.011"},{"key":"2022022208251488000_10.2.e003490.32","article-title":"Computational principles and practice for decoding immune contexture in the tumor microenvironment","volume":"22","author":"Zhang","year":"2021","journal-title":"Brief Bioinform"},{"key":"2022022208251488000_10.2.e003490.33","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/s41591-018-0136-1","article-title":"Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response","volume":"24","author":"Jiang","year":"2018","journal-title":"Nat Med"},{"key":"2022022208251488000_10.2.e003490.34"},{"key":"2022022208251488000_10.2.e003490.35","doi-asserted-by":"crossref","DOI":"10.1002\/advs.201902880","article-title":"ImmuCellAI: a unique method for comprehensive T-cell subsets abundance prediction and its application in cancer immunotherapy","volume":"7","author":"Miao","year":"2020","journal-title":"Adv Sci"},{"key":"2022022208251488000_10.2.e003490.36","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/mt.2016.67","article-title":"Predictive and prognostic clinical variables in cancer patients treated with adenoviral oncolytic immunotherapy","volume":"24","author":"Taipale","year":"2016","journal-title":"Mol Ther"},{"key":"2022022208251488000_10.2.e003490.37","doi-asserted-by":"crossref","first-page":"6320","DOI":"10.18632\/oncotarget.23967","article-title":"Interleukin 8 activity influences the efficacy of adenoviral oncolytic immunotherapy in cancer patients","volume":"9","author":"Taipale","year":"2018","journal-title":"Oncotarget"},{"key":"2022022208251488000_10.2.e003490.38","doi-asserted-by":"crossref","unstructured":"Han J , Khatwani N , Searles TG , et al . Memory CD8+ T cell responses to cancer. Semin Immunol 2020;49:101435. doi:10.1016\/j.smim.2020.101435","DOI":"10.1016\/j.smim.2020.101435"},{"key":"2022022208251488000_10.2.e003490.39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400348"},{"key":"2022022208251488000_10.2.e003490.40","doi-asserted-by":"crossref","DOI":"10.1038\/srep28208","article-title":"Na\u00efve CD8(+) T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-\u03b2 immunosuppression in the tumor microenvironment","volume":"6","author":"Nguyen","year":"2016","journal-title":"Sci Rep"},{"key":"2022022208251488000_10.2.e003490.41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/CJI.0000000000000147","article-title":"The characteristics of Naive-like T cells in tumor-infiltrating lymphocytes from human lung cancer","volume":"40","author":"Sheng","year":"2017","journal-title":"J Immunother"},{"key":"2022022208251488000_10.2.e003490.42","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002949"},{"key":"2022022208251488000_10.2.e003490.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.09.019"},{"key":"2022022208251488000_10.2.e003490.44","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1007\/s00262-015-1752-y","article-title":"Dysfunction of PSA-specific CD8+ T cells in prostate cancer patients correlates with CD38 and Tim-3 expression","volume":"64","author":"Japp","year":"2015","journal-title":"Cancer Immunol Immunother"},{"key":"2022022208251488000_10.2.e003490.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.034"},{"key":"2022022208251488000_10.2.e003490.46","doi-asserted-by":"crossref","DOI":"10.3390\/cells9071716","article-title":"CD38: T cell immuno-metabolic modulator","volume":"9","author":"Kar","year":"2020","journal-title":"Cells"},{"key":"2022022208251488000_10.2.e003490.47","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.144"},{"key":"2022022208251488000_10.2.e003490.48","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-17011-z","article-title":"Oncolytic virus-derived type I interferon restricts CAR T cell therapy","volume":"11","author":"Evgin","year":"2020","journal-title":"Nat Commun"},{"key":"2022022208251488000_10.2.e003490.49","article-title":"Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells","author":"Sumida","year":"2020","journal-title":"bioRxiv"},{"key":"2022022208251488000_10.2.e003490.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.08.027"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2021-003490","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T11:26:50Z","timestamp":1645529210000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2021-003490"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,22]]},"published-print":{"date-parts":[[2022,2]]}},"alternative-id":["10.1136\/jitc-2021-003490"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2021-003490","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2]]}}}