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We conducted a pan-cancer transcriptome analysis of CD40, its ligand, and related immune markers to evaluate co-expression patterns and clinical outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed transcriptome data for CD40, its ligand, and other common checkpoints and co-stimulators (PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, ICOS, CD27, CD28, OX40, and GITR). RNA expression was classified as high (75\u2013100th percentile), moderate (25\u201374th), or low (0\u201324th) against a reference population of 735 previously tested solid tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 514 patients, 114 (22%) showed high, 247 (48%) moderate, and 153 (30%) low CD40 RNA expression. High CD40 expression was most frequent in liver and bile duct (42%), pancreatic (42%), and ovarian (40%) cancers. Both high CD40 and low\u2013moderate CD40 ligand expression\u2014potentially conducive to CD40 agonist therapy\u2014was most frequent in ovarian (33%) and pancreatic (24%) cancer. In both UCSD (N\u2009=\u2009514) and TCGA (N\u2009=\u200910,953) cohorts, high CD40 expression significantly correlated with high CD28 and GITR. High CD40 RNA levels were not prognostic for overall survival (OS) from metastatic disease (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.2) (n\u2009=\u2009272 immune checkpoint inhibitor (ICI)-na\u00efve patients). High CD40 expression correlated with longer OS from immunotherapy initiation (n\u2009=\u2009217 ICI-treated patients;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.04, univariable analysis), but not multivariable analysis, suggesting it may not be an independent predictive biomarker.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>High CD40 expression correlated with liver and bile duct, pancreatic, and ovarian cancers, as well as with CD28 and GITR transcripts. Immune marker co-expression in individual patients merits further exploration for the development of CD40-based and other immunotherapy interventions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00262-025-04197-8","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T04:34:14Z","timestamp":1762144454000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["CD40 transcriptomic expression patterns across malignancies: implications for clinical trials of CD40 agonists"],"prefix":"10.1007","volume":"74","author":[{"given":"Yuji","family":"Uehara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Nishizaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Fujiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Miyashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanna","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarabjot","family":"Pabla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"DePietro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor J.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason K.","family":"Sicklick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumei","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razelle","family":"Kurzrock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"4197_CR1","doi-asserted-by":"publisher","first-page":"940674","DOI":"10.3389\/fimmu.2022.940674","volume":"13","author":"R Salomon","year":"2022","unstructured":"Salomon R, Dahan R (2022) Next generation CD40 agonistic antibodies for cancer immunotherapy. 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Dr. Fujiwara received expenses from Conquer Cancer, the ASCO Foundation outside the scope of this work. Dr. Kato serves as a consultant for Medpace, Foundation Medicine, NeoGenomics, and CureMatch. He receives speaker\u2019s fee from Roche and Bayer, and advisory board for Pfizer. He has research funding from ACT Genomics, Sysmex, Konica Minolta, OmniSeq, and Personalis. Dr. Sicklick receives research funding from Novartis Pharmaceuticals, Amgen Pharmaceuticals, and Foundation Medicine; consultant fees from Grand Rounds, Loxo, and Deciphera; and speaker\u2019s fees from Roche and Deciphera. He also owns stocks in Personalis. Dr. Kurzrock has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI; as well as consultant and\/or speaker fees and\/or advisory board\/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, EISAI, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Regeneron, Roche, TD2\/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch Inc. and IDbyDNA; serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. Dr. Pabla, Dr. Ko, Dr. DePietro, and Dr. Jensen are employees of Labcorp and may hold Labcorp stock. No potential conflict of interest were disclosed by the other authors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"359"}}