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Biol."],"published-print":{"date-parts":[[2026,4,1]]},"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 Rosenberg and Restifo (2015\n                    <jats:italic>Science<\/jats:italic>\n                    <jats:bold>348<\/jats:bold>\n                    62\u201368), Bonini and Mondino (2015\n                    <jats:italic>Eur. J. Immunol.<\/jats:italic>\n                    <jats:bold>45<\/jats:bold>\n                    2457\u201369). 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 Morgan\n                    <jats:italic>et al<\/jats:italic>\n                    (1976\n                    <jats:italic>Science<\/jats:italic>\n                    <jats:bold>193<\/jats:bold>\n                    1007\u20138). 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 Rosenberg\n                    <jats:italic>et al<\/jats:italic>\n                    (1985\n                    <jats:italic>J. Exp. Med.<\/jats:italic>\n                    <jats:bold>161<\/jats:bold>\n                    1169\u201388). 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 Donohue\n                    <jats:italic>et al<\/jats:italic>\n                    (1984\n                    <jats:italic>J. Immunol.<\/jats:italic>\n                    <jats:bold>132<\/jats:bold>\n                    2123\u20138). Based on the results,\n                    <jats:italic>CISH<\/jats:italic>\n                    knockout increases the transcription of activation biomarkers IL-2 and TNF-\n                    <jats:italic>\u03b1<\/jats:italic>\n                    , 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, 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":"10.1088\/1478-3975\/ae4705","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T22:55:02Z","timestamp":1771368902000},"page":"026003","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing"],"prefix":"10.1088","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9869-7664","authenticated-orcid":true,"given":"Nikolaos","family":"Memmos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8213-1797","authenticated-orcid":true,"given":"Kamran","family":"Kaveh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beau R","family":"Webber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Branden S","family":"Moriarity","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7731-2799","authenticated-orcid":true,"given":"David J","family":"Odde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"266","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"pbae4705bib1","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1126\/SCIENCE.AAA4967","type":"journal-article","article-title":"Adoptive cell transfer as personalized immunotherapy for human cancer","volume":"348","author":"Rosenberg","year":"2015","journal-title":"Science"},{"key":"pbae4705bib2","doi-asserted-by":"publisher","first-page":"2457","DOI":"10.1002\/EJI.201545552","type":"journal-article","article-title":"Adoptive T-cell therapy for cancer: the era of engineered T cells","volume":"45","author":"Bonini","year":"2015","journal-title":"Eur. 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