{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:34:59Z","timestamp":1791848099350,"version":"4.3.4"},"reference-count":99,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5U01CA180888\u201008"],"award-info":[{"award-number":["5U01CA180888\u201008"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5UG1CA233198\u201005"],"award-info":[{"award-number":["5UG1CA233198\u201005"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>ICOS (inducible T\u2010cell co\u2010stimulator) and ICOS ligand (ICOSL) are part of an important, complex pathway that can lead to both immune stimulation and suppression. ICOS and ICOSL have heterogeneous expression patterns between and within tumor types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This review provides an overview of ICOS and ICOSL, their mechanisms of action, expression in cancer and other diseases, and clinical trials exploring therapies targeting ICOS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Because of the bidirectional immune impact of the ICOS\/ICOSL signaling pathway, both ICOS agonists and antagonists are under development and evaluation in clinical trials. The majority of clinical trials have focused on the development of ICOS agonists, with only one study exploring an ICOS antagonist; there have been no clinical trials developing ICOSL agonists or antagonists in oncology. ICOS can be expressed on immune\u2010activating effector T\u2010cell and immunosuppressive regulatory T\u2010cell (Tregs). Thus, it is critical to determine where and how ICOS is expressed in order to evaluate the role for agonists versus antagonists. To date, ICOS agonists have shown limited activity in patients with malignancies, perhaps because of the lack of biomarker\u2010based trials. However, an ICOS antagonist demonstrated a 44% response rate in angioimmunoblastic T\u2010cell lymphoma; ICOS is highly expressed on T\u2010follicular helper cells (type of CD4 cell) and proliferation of these cells may be a pathogenic mechanism for these lymphomas. A role for the ICOS\/ICOSL signaling pathway has also been implicated outside of oncology, including in viral infections such as COVID\u201019, and in autoimmune conditions such as asthma and systemic lupus erythematosus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Biomarker\u2010driven approaches will be important to individualize therapy and ascertain which cancer patients will derive the greatest benefit from ICOS\u2010directed combination therapy approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71467","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T17:40:06Z","timestamp":1767202806000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Inducible T\u2010Cell Co\u2010Stimulator (\n                    <scp>ICOS<\/scp>\n                    ) and\n                    <scp>ICOS<\/scp>\n                    Ligand: Dealing With a Two\u2010Faced Cancer Immunoregulatory System"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7052-6348","authenticated-orcid":false,"given":"Mina","family":"Nikanjam","sequence":"first","affiliation":[{"name":"Division of Hematology\u2010Oncology University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumei","family":"Kato","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Nishizaki","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Miyashita","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Dartmouth Cancer Center  Lebanon New Hampshire USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarabjot","family":"Pabla","sequence":"additional","affiliation":[{"name":"OmniSeq (Labcorp) Inc.  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary K.","family":"Nesline","sequence":"additional","affiliation":[{"name":"Labcorp Oncology  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Ko","sequence":"additional","affiliation":[{"name":"Labcorp Oncology  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Conroy","sequence":"additional","affiliation":[{"name":"OmniSeq (Labcorp) Inc.  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4803-8513","authenticated-orcid":false,"given":"Aung","family":"Naing","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics MD Anderson Cancer Center  Houston California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razelle","family":"Kurzrock","sequence":"additional","affiliation":[{"name":"Medical College of Wisconsin Cancer Center  Milwaukee Wisconsin USA"},{"name":"WIN Consortium  Chevilly\u2010Larue France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.017"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3332\/ecancer.2020.1148"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-2182"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504030"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2109970"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3356"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002990"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.33591"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2019-000544"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.2.774"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.9.5035"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.1.132"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-20-0034"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911573106"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3050"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.4.2340"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.182.3.1421"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.03.023"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141432"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.017"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1403206"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100853"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13803"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12058"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/35051100"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/35051113"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni947"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-08-2416"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.6.3659"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/35051107"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2020.1693540"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/16717"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.180.6.2049"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00304"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3463"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0219449"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadva.2023.100103"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389203719666180608093913"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI123386"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01333-1"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200535571"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2013.05.021"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.3.1969"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-009-0090-7"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201816"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.04.011"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.11.017"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.05.013"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.12.7394"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.06.001"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2020.38.15_suppl.6517"},{"key":"e_1_2_12_53_1","volume-title":"Inducible T\u2010Cell Co\u2010Stimulatory (ICOS) Receptor Agonist, Feladilimab (Fela), Alone and in Combination (Combo) With Pembrolizumab (P): Results From INDUCE\u20101 Urothelial Carcinoma (UC) Expansion Cohorts (ECs)","author":"Balar A. V.","year":"2021"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-4256"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.TPS9137"},{"key":"e_1_2_12_56_1","volume-title":"Jounce Therapeutics Reports Results From Phase 2 Randomized SELECT Trial Testing 2 Different Doses of Vopratelimab in TISvopra Biomarker\u2010Selected Patients"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.16_suppl.2604"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-2955"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.2624"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002395"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1379"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035981"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2409"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2271"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.30475"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2015.1008355"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-2355"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2011.53"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1141857"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-06-508044"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0039.2006.00706.x"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2672"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.10291"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.02.017"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46266"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.5.2967"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905139106"},{"key":"e_1_2_12_78_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-0569"},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2848"},{"key":"e_1_2_12_80_1","doi-asserted-by":"publisher","DOI":"10.4161\/onci.23185"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0554"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2005"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0806075105"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-0505"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0020"},{"key":"e_1_2_12_86_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-1432"},{"key":"e_1_2_12_87_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.96976"},{"key":"e_1_2_12_88_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41525-023-00359-8"},{"key":"e_1_2_12_89_1","doi-asserted-by":"publisher","DOI":"10.1177\/17588359251330514"},{"key":"e_1_2_12_90_1","doi-asserted-by":"publisher","DOI":"10.1177\/17588359221133893"},{"key":"e_1_2_12_91_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005191"},{"key":"e_1_2_12_92_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni902"},{"key":"e_1_2_12_93_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar1928"},{"key":"e_1_2_12_94_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.22055"},{"key":"e_1_2_12_95_1","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2016-000146"},{"key":"e_1_2_12_96_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40479"},{"key":"e_1_2_12_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.02.007"},{"key":"e_1_2_12_98_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00595-007-3734-y"},{"key":"e_1_2_12_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-3274(03)00016-9"},{"key":"e_1_2_12_100_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.13100"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.71467","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.71467","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.71467","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:01:34Z","timestamp":1772967694000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.71467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,31]]},"references-count":99,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/cam4.71467"],"URL":"https:\/\/doi.org\/10.1002\/cam4.71467","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,31]]},"assertion":[{"value":"2024-12-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71467"}}