{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:24:11Z","timestamp":1785414251015,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,20]]},"group-title":"Immunology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01 CA189806"],"award-info":[{"award-number":["R01 CA189806"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,19]]},"abstract":"<jats:title>Abstract \/ Summary<\/jats:title>\n                <jats:p>\n                  Survival outcomes for pediatric Burkitt lymphoma (BL) substantially vary depending on geography (50-90%), which also serves as a proxy for the prevalence of Epstein-Barr virus (EBV) within the tumors. Although BL is considered an immunologically \u201ccold\u201d tumor with few tumor-infiltrating lymphocytes (TILs), their functional status has not been fully evaluated, especially for EBV-positive disease. Here, we characterize the exhaustion and activation profiles of T cells in the tumor microenvironment (TME) of EBV-positive BL using orthogonal methods, single-cell gene expression analysis, spectral flow cytometry, and immuno-histochemistry staining (IHC). We found that CD8+ TILs displayed a mosaic of immune inhibitory gene expression encoding,\n                  <jats:italic>PD1<\/jats:italic>\n                  ,\n                  <jats:italic>TIGIT<\/jats:italic>\n                  ,\n                  <jats:italic>LAG3<\/jats:italic>\n                  and\n                  <jats:italic>HAVCR2\/<\/jats:italic>\n                  TIM3. IHC validated the expression of PD1 and TIGIT on CD8+ TILs, as well as their respective ligands, PDL-1, PVR, and Nectin-2 on malignant B cells. Despite exhaustion-associated signatures, CD8+ TILs retain cytotoxic potential, expressing granules (i.e. Granzyme A, Perforin) and cytokines (i.e. IFN\u03b3) and demonstrate an increased uptake of metabolites such as glucose, arginine, and methionine. In peripheral blood, pediatric BL patients exhibited a significantly higher abundance of PD1+TIGIT+ CD8+ T cells compared to healthy children. Notably, these circulating T cells from BL patients express significantly lower levels of TOX, suggesting they are not irreversibly dysfunctional. Together, our results indicate that CD8+ T cells both in the TME and in circulation of children with BL are not terminally exhausted but remain poised for functional re-invigoration. These findings support the potential integration of immune checkpoint inhibitors into combination chemotherapeutic regimens to improve outcomes for these children.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>EBV-positive BL tumors contain functional, metabolically active CD8+ T cells.<\/jats:p>\n                  <jats:p>Circulating PD1+TIGIT+CD8+ T cells found in BL patients\u2019 blood are a biomarker for those in the tumor microenvironment.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.15.718702","type":"posted-content","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T18:15:16Z","timestamp":1776708916000},"source":"Crossref","is-referenced-by-count":0,"title":["Not so cold after all: tumor infiltrating CD8+ T cells in EBV-positive Burkitt lymphoma are quiescent, not exhausted"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7358-5546","authenticated-orcid":false,"given":"Catherine S.","family":"Forconi","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cliff I.","family":"Oduor","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya L.","family":"Saikumar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary 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Massachusetts Chan Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeni","family":"Melo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"L\u00e4derach","sequence":"additional","affiliation":[{"name":"Department of Viral Immunobiology, Institute of Experimental Immunology, University of Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Titus K.","family":"Maina","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana A.","family":"Otieno","sequence":"additional","affiliation":[{"name":"Jaramogi Oginga Odinga Teaching and Referral Hospital, Kisumu, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chepsiror","family":"Dan","sequence":"additional","affiliation":[{"name":"Moi Teaching and Referral Hospital, Eldoret, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kibet","family":"Kibor","sequence":"additional","affiliation":[{"name":"Moi Teaching and Referral Hospital, Eldoret, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Festus","family":"Njuguna","sequence":"additional","affiliation":[{"name":"Moi Teaching and Referral Hospital, Eldoret, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Vik","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann W.","family":"Kinyua","sequence":"additional","affiliation":[{"name":"Center for 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