{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:05:45Z","timestamp":1792785945156,"version":"4.5.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T00:00:00Z","timestamp":1745625600000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kathleen M. Rotz Lung Cancer Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tissue resident memory T cells (TRM) play a critical role in cancer immunity and their presence in solid tumors is associated with improved prognosis and response to therapy. Although TRM have been identified and their function characterized in lung cancers, little is known regarding TRM outside of a tissue context, such as within malignant pleural effusions (MPE). As MPE are routinely drained and collected to manage symptoms, analysis of this fluid can provide an insight into the peri-tumoral environment. In this study, we performed flow cytometry and single cell RNAseq (scRNAseq) on MPE associated with non-small lung cancer and examined the phenotype and function of TRM. We found that 14% of CD8+ T cells and 6% of CD4+ T cells were TRM, as defined by the phenotype of CD45RO+CCR7-CD62L- and expressing 1 or both of CD69 and CD103. The scRNAseq revealed distinct clusters expressing TRM-associated genes including ITGAE and CD49A and lacking expression of SELL, CCR7, and IL7RA. TRM did not differ from other memory T cell subsets, such as T central memory (TCM) and T effector memory (TEM) cells, in expression of the inhibitory markers PD-1, TIGIT, and CD39. When TRM function was assessed by measuring the production of IFN-\u03b3, TNF-\u03b1, and CD107a after stimulation with \u03b1nti-CD3 antibodies in vitro, TRM had comparable function to T effector cells (TE), indicating that despite expression of exhaustion markers these cells retained effector function. Finally, we found that CD69 expression, and not CD103 expression, on TRM was associated with production of effector cytokines.<\/jats:p>","DOI":"10.1093\/immhor\/vlaf013","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T03:16:54Z","timestamp":1745637414000},"source":"Crossref","is-referenced-by-count":9,"title":["Identification and characterization of tissue resident memory T cells in malignant pleural effusions associated with non-small cell lung cancer"],"prefix":"10.1093","volume":"9","author":[{"given":"Caitlin M","family":"Tilsed","sequence":"first","affiliation":[{"name":"Pulmonary, Critical Care, and Allergy Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Brotman","sequence":"additional","affiliation":[{"name":"Pulmonary, Critical Care, and Allergy Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Informatics and Predictive Sciences, Mechanisms of Cancer Resistance, Bristol Myers Squibb , Cambridge, MA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brennan","family":"Lee","sequence":"additional","affiliation":[{"name":"Informatics and Predictive Sciences, Mechanisms of Cancer Resistance, Bristol Myers Squibb , Cambridge, MA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmund","family":"Moon","sequence":"additional","affiliation":[{"name":"Pulmonary, Critical Care, and Allergy Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M","family":"Albelda","sequence":"additional","affiliation":[{"name":"Pulmonary, Critical Care, and Allergy Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"2025042603164662300_vlaf013-B1","doi-asserted-by":"crossref","first-page":"eabo5871","DOI":"10.1126\/sciadv.abo5871","article-title":"The evolving role of tissue-resident memory T cells in infections and cancer","volume":"8","author":"Yenyuwadee","year":"2022","journal-title":"Sci. Adv"},{"key":"2025042603164662300_vlaf013-B2","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/s00281-022-00970-4","article-title":"Human T lymphocytes at tumor sites","volume":"44","author":"Notarbartolo","year":"2022","journal-title":"Semin Immunopathol"},{"key":"2025042603164662300_vlaf013-B3","doi-asserted-by":"crossref","first-page":"1205984","DOI":"10.3389\/fimmu.2023.1205984","article-title":"Tumor-resident memory T cells as a biomarker of the response to cancer immunotherapy","volume":"14","author":"Damei","year":"2023","journal-title":"Front Immunol"},{"key":"2025042603164662300_vlaf013-B4","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.1158\/1078-0432.CCR-17-2257","article-title":"CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy-na\u00efve melanoma patients and expand significantly during anti-PD-1 treatment","volume":"24","author":"Edwards","year":"2018","journal-title":"Clin Cancer Res"},{"key":"2025042603164662300_vlaf013-B5","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1097\/IGC.0000000000000672","article-title":"Combined immunoscore of CD103 and CD3 identifies long-term survivors in high-grade serous ovarian cancer","volume":"26","author":"B\u00f6sm\u00fcller","year":"2016","journal-title":"Int J Gynecol Cancer"},{"key":"2025042603164662300_vlaf013-B6","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/s41591-018-0078-7","article-title":"Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis","volume":"24","author":"Savas","year":"2018","journal-title":"Nat Med"},{"key":"2025042603164662300_vlaf013-B7","doi-asserted-by":"crossref","first-page":"573","DOI":"10.3389\/fimmu.2016.00573","article-title":"Very late antigen-1 marks functional tumor-resident CD8 T cells and correlates with survival of melanoma patients","volume":"7","author":"Murray","year":"2016","journal-title":"Front Immunol"},{"key":"2025042603164662300_vlaf013-B8","doi-asserted-by":"crossref","first-page":"100127","DOI":"10.1016\/j.xcrm.2020.100127","article-title":"CD103+CD8+ TRM cells accumulate in tumors of anti-PD-1-responder lung cancer patients and are tumor-reactive lymphocytes enriched with Tc17","volume":"1","author":"Corgnac","year":"2020","journal-title":"Cell Rep Med"},{"key":"2025042603164662300_vlaf013-B9","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1016\/j.celrep.2017.08.078","article-title":"Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites","volume":"20","author":"Kumar","year":"2017","journal-title":"Cell Rep"},{"key":"2025042603164662300_vlaf013-B10","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1126\/science.1208248","article-title":"GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood","volume":"333","author":"Arnon","year":"2011","journal-title":"Science"},{"key":"2025042603164662300_vlaf013-B11","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nature04606","article-title":"CD69 acts downstream of interferon-alpha\/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs","volume":"440","author":"Shiow","year":"2006","journal-title":"Nature"},{"key":"2025042603164662300_vlaf013-B12","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1016\/j.jaci.2018.11.048","article-title":"Inhibitory checkpoint receptors control CD8+ resident memory T cells to prevent skin allergy","volume":"143","author":"Gamradt","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"2025042603164662300_vlaf013-B13","doi-asserted-by":"crossref","first-page":"279ra39","DOI":"10.1126\/scitranslmed.3010302","article-title":"Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells","volume":"7","author":"Watanabe","year":"2015","journal-title":"Sci Transl Med"},{"key":"2025042603164662300_vlaf013-B14","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1158\/2326-6066.CIR-18-0713","article-title":"Function of human tumor-infiltrating lymphocytes in early-stage non\u2013small cell lung cancer","volume":"7","author":"O\u2019Brien","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"2025042603164662300_vlaf013-B15","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.4049\/jimmunol.1402711","article-title":"CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients","volume":"194","author":"Djenidi","year":"2015","journal-title":"J Immunol."},{"key":"2025042603164662300_vlaf013-B16","doi-asserted-by":"crossref","first-page":"672747","DOI":"10.3389\/fonc.2021.672747","article-title":"Malignant pleural effusions\u2014a window into local anti-tumor T cell immunity?","volume":"11","author":"Principe","year":"2021","journal-title":"Front Oncol"},{"key":"2025042603164662300_vlaf013-B17","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.jtho.2019.03.029","article-title":"Potential diagnostic and prognostic role of microenvironment in malignant pleural mesothelioma","volume":"14","author":"Salaroglio","year":"2019","journal-title":"J Thorac Oncol."},{"key":"2025042603164662300_vlaf013-B18","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s00262-021-02994-5","article-title":"Eosinophilic pleural effusion due to lung cancer has a better prognosis than non-eosinophilic malignant pleural effusion","volume":"71","author":"Takeuchi","year":"2022","journal-title":"Cancer Immunol Immunother."},{"key":"2025042603164662300_vlaf013-B19","doi-asserted-by":"crossref","first-page":"1031094","DOI":"10.3389\/fonc.2022.1031094","article-title":"Lung adenocarcinoma patients with malignant pleural effusions in hot adaptive immunity status have a longer overall survival","volume":"12","author":"Wu","year":"2022","journal-title":"Front Oncol"},{"key":"2025042603164662300_vlaf013-B20","doi-asserted-by":"crossref","first-page":"9381","DOI":"10.1038\/s41598-021-89043-4","article-title":"Higher CD4\/CD8 ratio of pleural effusion predicts better survival for lung cancer patients receiving immune checkpoint inhibitors","volume":"11","author":"Lee","year":"2021","journal-title":"Sci Rep"},{"key":"2025042603164662300_vlaf013-B21","doi-asserted-by":"crossref","first-page":"e1356","DOI":"10.1002\/ctm2.1356","article-title":"Single-cell RNA sequencing captures patient-level heterogeneity and associated molecular phenotypes in breast cancer pleural effusions","volume":"13","author":"Whitfield","year":"2023","journal-title":"Clin Transl Med"},{"key":"2025042603164662300_vlaf013-B22","doi-asserted-by":"crossref","first-page":"6690","DOI":"10.1038\/s41467-021-27026-9","article-title":"Single-cell analysis of diverse immune phenotypes in malignant pleural effusion","volume":"12","author":"Huang","year":"2021","journal-title":"Nat Commun"},{"key":"2025042603164662300_vlaf013-B23","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Hao","year":"2024","journal-title":"Nat Biotechnol"},{"key":"2025042603164662300_vlaf013-B24","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat Immunol"},{"key":"2025042603164662300_vlaf013-B25","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.3390\/cells10082143","article-title":"Single-cell transcriptomics reveals core regulatory programs that determine the heterogeneity of circulating and tissue-resident memory CD8+ T cells","volume":"10","author":"Chen","year":"2021","journal-title":"Cells"},{"key":"2025042603164662300_vlaf013-B26","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/44385","article-title":"Two subsets of memory T lymphocytes with distinct homing potentials and effector functions","volume":"401","author":"Sallusto","year":"1999","journal-title":"Nature"},{"key":"2025042603164662300_vlaf013-B27","doi-asserted-by":"crossref","first-page":"8068","DOI":"10.3390\/ijms22158068","article-title":"CD39 regulation and functions in T cells","volume":"22","author":"Timperi","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2025042603164662300_vlaf013-B28","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/s43018-021-00180-1","article-title":"Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy","volume":"2","author":"Han","year":"2021","journal-title":"Nat Cancer"},{"key":"2025042603164662300_vlaf013-B29","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.7150\/jca.83615","article-title":"Tissue resident memory T cells are enriched and dysfunctional in effusion of patients with malignant tumor","volume":"14","author":"Mao","year":"2023","journal-title":"J Cancer"},{"key":"2025042603164662300_vlaf013-B30","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.3389\/fimmu.2018.02654","article-title":"Functional heterogeneity of CD4+ tumor-infiltrating lymphocytes with a resident memory phenotype in NSCLC","volume":"9","author":"Oja","year":"2018","journal-title":"Front Immunol"},{"key":"2025042603164662300_vlaf013-B31","doi-asserted-by":"crossref","first-page":"6643808","DOI":"10.1155\/2021\/6643808","article-title":"Tissue-resident memory-like CD8+ T cells exhibit heterogeneous characteristics in tuberculous pleural effusion","volume":"2021","author":"Yu","year":"2021","journal-title":"J Immunol Res"},{"key":"2025042603164662300_vlaf013-B32","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1158\/1078-0432.CCR-03-0239","article-title":"Characterization of effusion-infiltrating T cells: benign versus malignant effusions","volume":"10","author":"Atanackovic","year":"2004","journal-title":"Clin Cancer Res"},{"key":"2025042603164662300_vlaf013-B33","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.lungcan.2004.07.046","article-title":"Effector, memory and na\u00efve CD8+ T cells in peripheral blood and pleural effusion from lung adenocarcinoma patients","volume":"47","author":"Prado-Garcia","year":"2005","journal-title":"Lung Cancer"},{"key":"2025042603164662300_vlaf013-B34","doi-asserted-by":"crossref","first-page":"e1072","DOI":"10.1002\/ctm2.1072","article-title":"Characterization of the tumour microenvironment phenotypes in malignant tissues and pleural effusion from advanced osteoblastic osteosarcoma patients","volume":"12","author":"Zhang","year":"2022","journal-title":"Clin Transl Med"},{"key":"2025042603164662300_vlaf013-B35","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ygyno.2010.05.016","article-title":"Profound elevation of CD8+ T cells expressing the intraepithelial lymphocyte marker CD103 (alphaE\/beta7 Integrin) in high-grade serous ovarian cancer","volume":"118","author":"Webb","year":"2010","journal-title":"Gynecol Oncol"},{"key":"2025042603164662300_vlaf013-B36","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1186\/s13104-018-3953-x","article-title":"Tumour associated lymphocytes in the pleural effusions of patients with mesothelioma express high levels of inhibitory receptors","volume":"11","author":"Chee","year":"2018","journal-title":"BMC Res Notes"},{"key":"2025042603164662300_vlaf013-B37","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1084\/jem.20190249","article-title":"Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer","volume":"216","author":"Clarke","year":"2019","journal-title":"J Exp Med"},{"key":"2025042603164662300_vlaf013-B38","doi-asserted-by":"crossref","first-page":"e009440","DOI":"10.1136\/jitc-2024-009440","article-title":"Differential predictive value of resident memory CD8+ T cell subpopulations in patients with non-small-cell lung cancer treated by immunotherapy","volume":"12","author":"Paolini","year":"2024","journal-title":"J Immunother Cancer"},{"key":"2025042603164662300_vlaf013-B39","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.immuni.2024.11.007","article-title":"Deep profiling deconstructs features associated with memory CD8+ T cell tissue residence","volume":"58","author":"Scott","year":"2025","journal-title":"Immunity"},{"key":"2025042603164662300_vlaf013-B40","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1038\/s41467-018-05072-0","article-title":"Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors","volume":"9","author":"Duhen","year":"2018","journal-title":"Nat Commun"}],"container-title":["ImmunoHorizons"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article-pdf\/9\/6\/vlaf013\/63012825\/vlaf013.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article-pdf\/9\/6\/vlaf013\/63012825\/vlaf013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T03:16:59Z","timestamp":1745637419000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article\/doi\/10.1093\/immhor\/vlaf013\/8120279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,24]]},"references-count":40,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,4,26]]}},"URL":"https:\/\/doi.org\/10.1093\/immhor\/vlaf013","relation":{},"ISSN":["2573-7732"],"issn-type":[{"value":"2573-7732","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6]]},"published":{"date-parts":[[2025,4,24]]},"article-number":"vlaf013"}}