{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T11:09:03Z","timestamp":1776596943158,"version":"3.51.2"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T00:00:00Z","timestamp":1649808000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["R01\u2010CA175517\u201006"],"award-info":[{"award-number":["R01\u2010CA175517\u201006"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["RO1\u2010NS108781\u201003"],"award-info":[{"award-number":["RO1\u2010NS108781\u201003"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Microbiology and Immunology"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adoptive T\u2010cell therapies have been successfully used as prophylaxis or treatment for immunocompromised patients at risk of viral infections or advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors are used to rescue immune antitumor responses. We hypothesized that <jats:italic>in vitro<\/jats:italic> checkpoint blockade during T\u2010cell stimulation and expansion with messenger RNA (mRNA)\u2013pulsed DCs may enhance the activity of antigen\u2010specific T cells and improve the efficacy of adoptive cellular therapy platforms. Human peripheral blood mononuclear cells were isolated from cytomegalovirus (CMV)\u2010seropositive donors to generate DCs. These were pulsed with CMV matrix phosphoprotein 65 (CMVpp65)\u2010mRNA to educate T cells in coculture for 15 days. Three checkpoint blockade conditions were evaluated (anti\u2010PD1, anti\u2010Tim3, and anti\u2010PD1\u2009+\u2009Tim3). IL\u20102 and antibodies blockades were added every 3 days. Immunophenotyping was performed on Day 0 and Day 15. Polyfunctional antigen\u2010specific responses were evaluated upon rechallenge with CMVpp65 peptides. CMVpp65\u2010activated CD8<jats:sup>+<\/jats:sup> T cells upregulate Lag3 and Tim3 (<jats:italic>P<\/jats:italic>\u2009\u2264\u20090.0001). Tim3 antibody blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8<jats:sup>+<\/jats:sup> pp65Tetramer<jats:sup>+<\/jats:sup> central memory, effector memory, and terminal effector memory cells re\u2010expressing RA (TEMRA) T cells. This latter T\u2010cell subset uniquely maintains double\u2010positive Tim3\/Lag3 expression after checkpoint blockade. By contrast, PD1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN\u2010\u03b3 secretion was reduced in T cells treated with Tim3 blockade in a dose\u2010dependent manner (<jats:italic>P<\/jats:italic>\u2009=\u20090.004). In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking the Tim3 axis during T\u2010cell\u2013antigen\u2010presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.<\/jats:p>","DOI":"10.1111\/1348-0421.12967","type":"journal-article","created":{"date-parts":[[2022,2,12]],"date-time":"2022-02-12T11:58:42Z","timestamp":1644667122000},"page":"201-211","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Effects of immune checkpoint blockade on antigen\u2010specific CD8<sup>+<\/sup> T cells for use in adoptive cellular therapy"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7192-6714","authenticated-orcid":false,"given":"Elizabeth","family":"Ogando\u2010Rivas","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Brain Tumor Immunotherapy Program, Preston A. Wells Jr. Center for Brain Tumor Therapy, Lillian S. Wells, McKnight Brain Institute University of Florida Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Castillo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology Oncology University of Florida Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noah","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology Oncology University of Florida Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vrunda","family":"Trivedi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Tumor Immunotherapy Program, Preston A. Wells Jr. Center for Brain Tumor Therapy, Lillian S. Wells, McKnight Brain Institute University of Florida Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Drake","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Tumor Immunotherapy Program, Preston A. Wells Jr. Center for Brain Tumor Therapy, Lillian S. Wells, McKnight Brain Institute University of Florida Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anjelika","family":"Dechkovskaia","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Tumor Immunotherapy Program, Preston A. Wells Jr. Center for Brain Tumor Therapy, Lillian S. Wells, McKnight Brain Institute University of Florida Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate M.","family":"Candelario","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Tumor Immunotherapy Program, Preston A. 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