{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:59:32Z","timestamp":1782280772783,"version":"3.54.5"},"posted":{"date-parts":[[2025,9,10]]},"group-title":"Immunology","reference-count":101,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy, where the lymphocytes of a cancer patient\u2019s tumor are harvested, expanded\n                  <jats:italic>in vitro<\/jats:italic>\n                  using IL-2 stimulation, and then infused back into the patient[1], [2]. However, even with the use of TIL therapy, cancer cells can survive for various reasons, such as poor lymphocyte infiltration into tumors, chronic activation of the T cell receptor and the immunosuppressive tumor microenvironment[3]. Cytokine-inducible SH2-containing (CISH) protein is a negative regulator of T cell activation, and in a recent clinical trial was knocked out in TILs to improve TIL therapy efficacy[4]. A mechanistic signaling pathway model was developed to theoretically evaluate the efficacy of\n                  <jats:italic>CISH<\/jats:italic>\n                  knockout (\n                  <jats:italic>CISH<\/jats:italic>\n                  KO) in T cell activation and examine potential alternative target genes that can theoretically be targeted using multiplex gene-editing or drugs to further improve T cell activation and function[5]. Based on the results,\n                  <jats:italic>CISH<\/jats:italic>\n                  knockout increases the transcription of activation biomarkers IL-2 and TNF-\u03b1, but also inhibitory biomarkers such as PD1 and FasL. Using global sensitivity analysis, we also found that\n                  <jats:italic>GSK3B<\/jats:italic>\n                  , which is responsible for the deactivation of NFAT, is also predicted to further increase T cell activation when knocked out. In addition, it was predicted that\n                  <jats:italic>PDCD1<\/jats:italic>\n                  ,\n                  <jats:italic>FAS<\/jats:italic>\n                  and\n                  <jats:italic>CTLA4<\/jats:italic>\n                  can be knocked out in combination with\n                  <jats:italic>CISH<\/jats:italic>\n                  to further enhance T cell activation and prevent exhaustion and apoptosis.\n                <\/jats:p>","DOI":"10.1101\/2025.09.05.674558","type":"posted-content","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T07:20:22Z","timestamp":1757575222000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing"],"prefix":"10.64898","author":[{"given":"Nikolaos","family":"Memmos","sequence":"first","affiliation":[{"name":"University of Minnesota, Department of Biomedical Engineering, Minneapolis, Minnesota, USA"},{"name":"University of Minnesota, Therapy Modeling and Design Center, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamran","family":"Kaveh","sequence":"additional","affiliation":[{"name":"University of Minnesota, Therapy Modeling and Design Center, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beau R.","family":"Webber","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Pediatrics, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Branden S.","family":"Moriarity","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Pediatrics, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7731-2799","authenticated-orcid":false,"given":"David J.","family":"Odde","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Biomedical Engineering, Minneapolis, Minnesota, USA"},{"name":"University of Minnesota, Therapy Modeling and Design Center, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026011211400773000_2025.09.05.674558v3.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4967"},{"key":"2026011211400773000_2025.09.05.674558v3.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.181845"},{"key":"2026011211400773000_2025.09.05.674558v3.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.02.008"},{"key":"2026011211400773000_2025.09.05.674558v3.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(25)00083-X"},{"key":"2026011211400773000_2025.09.05.674558v3.5","doi-asserted-by":"publisher","DOI":"10.1038\/S41598-019-46592-Z"},{"key":"2026011211400773000_2025.09.05.674558v3.6","doi-asserted-by":"publisher","DOI":"10.1002\/EJI.201545552"},{"key":"2026011211400773000_2025.09.05.674558v3.7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.161.5.1169"},{"key":"2026011211400773000_2025.09.05.674558v3.8","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.132.4.2123"},{"key":"2026011211400773000_2025.09.05.674558v3.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198512053132327"},{"key":"2026011211400773000_2025.09.05.674558v3.10","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/85.8.622"},{"key":"2026011211400773000_2025.09.05.674558v3.11","doi-asserted-by":"publisher","DOI":"10.1126\/science.3489291"},{"key":"2026011211400773000_2025.09.05.674558v3.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198812223192527"},{"key":"2026011211400773000_2025.09.05.674558v3.13","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.1076514"},{"key":"2026011211400773000_2025.09.05.674558v3.14","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3161"},{"key":"2026011211400773000_2025.09.05.674558v3.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0040-8"},{"key":"2026011211400773000_2025.09.05.674558v3.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1609279"},{"key":"2026011211400773000_2025.09.05.674558v3.17","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005755"},{"key":"2026011211400773000_2025.09.05.674558v3.18","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02170"},{"key":"2026011211400773000_2025.09.05.674558v3.19","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150304"},{"key":"2026011211400773000_2025.09.05.674558v3.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.1.114"},{"key":"2026011211400773000_2025.09.05.674558v3.21","doi-asserted-by":"publisher","DOI":"10.1038\/43206"},{"key":"2026011211400773000_2025.09.05.674558v3.22","doi-asserted-by":"publisher","DOI":"10.1038\/43213"},{"key":"2026011211400773000_2025.09.05.674558v3.23","doi-asserted-by":"publisher","DOI":"10.1038\/43219"},{"key":"2026011211400773000_2025.09.05.674558v3.24","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3470"},{"key":"2026011211400773000_2025.09.05.674558v3.25","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3519"},{"key":"2026011211400773000_2025.09.05.674558v3.26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.43.28185"},{"key":"2026011211400773000_2025.09.05.674558v3.27","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.9.6396"},{"key":"2026011211400773000_2025.09.05.674558v3.28","doi-asserted-by":"publisher","DOI":"10.1016\/J.MEDJ.2022.07.008"},{"key":"2026011211400773000_2025.09.05.674558v3.29","doi-asserted-by":"publisher","DOI":"10.1016\/J.CYTO.2016.08.003"},{"key":"2026011211400773000_2025.09.05.674558v3.30","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.179.1.154"},{"key":"2026011211400773000_2025.09.05.674558v3.31","doi-asserted-by":"publisher","DOI":"10.1016\/J.IT.2023.09.003\/ASSET\/94B18407-EFBC-4066-B52A-82ED670C9C48\/MAIN.ASSETS\/GR4.JPG"},{"key":"2026011211400773000_2025.09.05.674558v3.32","doi-asserted-by":"publisher","DOI":"10.1146\/ANNUREV-IMMUNOL-042617-053352"},{"key":"2026011211400773000_2025.09.05.674558v3.33","doi-asserted-by":"publisher","DOI":"10.2174\/1874210601913010332"},{"key":"2026011211400773000_2025.09.05.674558v3.34","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2018.00444\/PDF"},{"key":"2026011211400773000_2025.09.05.674558v3.35","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.14870"},{"key":"2026011211400773000_2025.09.05.674558v3.36","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1514296"},{"key":"2026011211400773000_2025.09.05.674558v3.37","doi-asserted-by":"publisher","DOI":"10.1038\/nri3405"},{"key":"2026011211400773000_2025.09.05.674558v3.38","doi-asserted-by":"publisher","DOI":"10.1084\/JEM.20221391"},{"key":"2026011211400773000_2025.09.05.674558v3.39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.6.3831"},{"key":"2026011211400773000_2025.09.05.674558v3.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2007.02.003"},{"key":"2026011211400773000_2025.09.05.674558v3.41","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2016.00382"},{"key":"2026011211400773000_2025.09.05.674558v3.42","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80479-3"},{"key":"2026011211400773000_2025.09.05.674558v3.43","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.1.99"},{"key":"2026011211400773000_2025.09.05.674558v3.44","doi-asserted-by":"publisher","DOI":"10.46439\/cancerbiology.5.058"},{"key":"2026011211400773000_2025.09.05.674558v3.45","doi-asserted-by":"publisher","DOI":"10.1137\/141000671"},{"key":"2026011211400773000_2025.09.05.674558v3.46","doi-asserted-by":"publisher","DOI":"10.5334\/JORS.151"},{"key":"2026011211400773000_2025.09.05.674558v3.47","doi-asserted-by":"publisher","DOI":"10.1016\/S1352-2310(97)83212-8"},{"key":"2026011211400773000_2025.09.05.674558v3.48","doi-asserted-by":"publisher","DOI":"10.1137\/S1064827594276424"},{"key":"2026011211400773000_2025.09.05.674558v3.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.advengsoft.2019.03.009"},{"key":"2026011211400773000_2025.09.05.674558v3.50","doi-asserted-by":"publisher","DOI":"10.1016\/J.CAMWA.2011.06.002"},{"key":"2026011211400773000_2025.09.05.674558v3.51","doi-asserted-by":"publisher","DOI":"10.1137\/080743627"},{"key":"2026011211400773000_2025.09.05.674558v3.52","doi-asserted-by":"publisher","DOI":"10.1186\/S12979-020-00203-Y"},{"key":"2026011211400773000_2025.09.05.674558v3.53","doi-asserted-by":"publisher","DOI":"10.1038\/nm1293"},{"key":"2026011211400773000_2025.09.05.674558v3.54","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3182"},{"key":"2026011211400773000_2025.09.05.674558v3.55","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101804"},{"key":"2026011211400773000_2025.09.05.674558v3.56","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PCBI.0030189"},{"key":"2026011211400773000_2025.09.05.674558v3.57","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PCBI.1010322"},{"key":"2026011211400773000_2025.09.05.674558v3.58","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz581"},{"key":"2026011211400773000_2025.09.05.674558v3.59","doi-asserted-by":"publisher","DOI":"10.1137\/1.9781611971484"},{"key":"2026011211400773000_2025.09.05.674558v3.60","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PCBI.1008646"},{"key":"2026011211400773000_2025.09.05.674558v3.61","doi-asserted-by":"publisher","DOI":"10.2307\/1269043"},{"key":"2026011211400773000_2025.09.05.674558v3.62","doi-asserted-by":"publisher","DOI":"10.1002\/9780470725184"},{"key":"2026011211400773000_2025.09.05.674558v3.63","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"2026011211400773000_2025.09.05.674558v3.64","unstructured":"\u2018WebPlotDigitizer\u2019. Accessed: Feb. 24, 2025. [Online]. Available: https:\/\/automeris.io\/docs\/#cite-webplotdigitizer"},{"key":"2026011211400773000_2025.09.05.674558v3.65","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00834-9"},{"key":"2026011211400773000_2025.09.05.674558v3.66","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00833-2"},{"key":"2026011211400773000_2025.09.05.674558v3.67","doi-asserted-by":"publisher","DOI":"10.1038\/nature05316"},{"key":"2026011211400773000_2025.09.05.674558v3.68","doi-asserted-by":"publisher","DOI":"10.1101\/2021.08.17.456714"},{"key":"2026011211400773000_2025.09.05.674558v3.69","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10600-7"},{"key":"2026011211400773000_2025.09.05.674558v3.70","doi-asserted-by":"publisher","DOI":"10.1101\/2025.04.26.650767"},{"key":"2026011211400773000_2025.09.05.674558v3.71","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090880"},{"key":"2026011211400773000_2025.09.05.674558v3.72","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2404661121"},{"key":"2026011211400773000_2025.09.05.674558v3.73","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2023.1296341\/PDF"},{"key":"2026011211400773000_2025.09.05.674558v3.74","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2019.1571892"},{"key":"2026011211400773000_2025.09.05.674558v3.75","doi-asserted-by":"publisher","DOI":"10.1002\/IJC.33415"},{"key":"2026011211400773000_2025.09.05.674558v3.76","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.018"},{"key":"2026011211400773000_2025.09.05.674558v3.77","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2017.01653"},{"key":"2026011211400773000_2025.09.05.674558v3.78","doi-asserted-by":"publisher","DOI":"10.1016\/J.SMIM.2019.101295"},{"key":"2026011211400773000_2025.09.05.674558v3.79","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0491"},{"key":"2026011211400773000_2025.09.05.674558v3.80","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.018"},{"key":"2026011211400773000_2025.09.05.674558v3.81","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.01.076"},{"key":"2026011211400773000_2025.09.05.674558v3.82","doi-asserted-by":"publisher","DOI":"10.1186\/s13104-020-04971-0"},{"key":"2026011211400773000_2025.09.05.674558v3.83","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.672356"},{"key":"2026011211400773000_2025.09.05.674558v3.84","doi-asserted-by":"publisher","DOI":"10.1177\/17588359231220510"},{"key":"2026011211400773000_2025.09.05.674558v3.85","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2023.1158105\/FULL"},{"key":"2026011211400773000_2025.09.05.674558v3.86","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0768-9"},{"key":"2026011211400773000_2025.09.05.674558v3.87","doi-asserted-by":"publisher","DOI":"10.3390\/IJMS20040824"},{"key":"2026011211400773000_2025.09.05.674558v3.88","doi-asserted-by":"publisher","DOI":"10.1016\/J.EJCA.2020.03.029"},{"key":"2026011211400773000_2025.09.05.674558v3.89","doi-asserted-by":"publisher","DOI":"10.1038\/S41598-020-63796-W"},{"key":"2026011211400773000_2025.09.05.674558v3.90","doi-asserted-by":"publisher","DOI":"10.1126\/science.291.5502.319"},{"key":"2026011211400773000_2025.09.05.674558v3.91","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80406-9"},{"key":"2026011211400773000_2025.09.05.674558v3.92","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.1401686"},{"key":"2026011211400773000_2025.09.05.674558v3.93","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040036"},{"key":"2026011211400773000_2025.09.05.674558v3.94","doi-asserted-by":"publisher","DOI":"10.1109\/ALIFE.2007.367795"},{"key":"2026011211400773000_2025.09.05.674558v3.95","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20145794"},{"key":"2026011211400773000_2025.09.05.674558v3.96","doi-asserted-by":"publisher","DOI":"10.1126\/science.1176343"},{"key":"2026011211400773000_2025.09.05.674558v3.97","unstructured":"J.-M. Anaya , Y. Shoenfeld , A. Rojas-Villarraga , R. A. Levy , and R. Cervera , \u201cAutoimmunity,\u201d Autoimmunity: From Bench to Bedside, pp. 237\u2013378, Jul. 2013, Accessed: Jun. 11, 2025. [Online]. Available: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK459447\/"},{"key":"2026011211400773000_2025.09.05.674558v3.98","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1514240113"},{"key":"2026011211400773000_2025.09.05.674558v3.99","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.092538799"},{"key":"2026011211400773000_2025.09.05.674558v3.100","doi-asserted-by":"publisher","DOI":"10.1021\/pr101183k"},{"key":"2026011211400773000_2025.09.05.674558v3.101","doi-asserted-by":"publisher","DOI":"10.1038\/S41598-019-46592-Z"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.09.05.674558","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:07:13Z","timestamp":1782277633000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.09.05.674558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":101,"URL":"https:\/\/doi.org\/10.1101\/2025.09.05.674558","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1088\/1478-3975\/ae4705","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,9,10]]},"subtype":"preprint"}}