{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:20Z","timestamp":1792787300196,"version":"4.5.0"},"reference-count":32,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"unspecified","delay-in-days":17,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["09150161810003"],"award-info":[{"award-number":["09150161810003"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stichting Fonds Oncologie Holland","award":["22-01"],"award-info":[{"award-number":["22-01"]}]},{"name":"Leiden University Fund","award":["W20361-2-38"],"award-info":[{"award-number":["W20361-2-38"]}],"id":[{"id":"https:\/\/ror.org\/027bh9e22","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,8,29]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>Older adults with frailty demonstrate systemic immunosenescence, including T-cell exhaustion and reduced immune diversity, yet maintain immune checkpoint blockade (ICB) efficacy comparable to that of younger patients. Baseline immune cell composition in both the tumor microenvironment (TME) and peripheral blood has been linked to ICB response in melanoma. To address this paradox, we investigated whether frailty is associated with alterations in the TME immune composition in melanoma.<\/jats:p>\n                  <jats:p>We applied imaging mass cytometry with a 40-marker panel to comprehensively characterize the pretreatment immune TME in formalin-fixed, paraffin-embedded tissue from 23 patients with melanoma, stratified by age, frailty status (as determined by the Clinical Frailty Scale), and clinical benefit from ICB. 33 immune cell phenotypes were identified and compared across patient groups.<\/jats:p>\n                  <jats:p>\n                    Frail patients exhibited significantly higher densities of CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD45RO\n                    <jats:sup>+<\/jats:sup>\n                    memory T cells compared with non-frail older patients. No other differences in the immune TME were observed between frail and non-frail patients, and overall survival was comparable between these groups. In contrast, multiple age-related differences were observed, including reduced naive T-cell densities and increased myeloid cell infiltration in older patients, consistent with features of immunologic aging. Clinical benefit from ICB was associated with greater overall immune infiltration and lower granulocyte densities, independent of age or frailty status.\n                  <\/jats:p>\n                  <jats:p>Despite previously demonstrated systemic immunosenescence, the melanoma immune TME preserved in older adults with frailty, consistent with observed preservation of ICB efficacy.<\/jats:p>","DOI":"10.1136\/jitc-2026-015212","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T13:20:15Z","timestamp":1789737615000},"page":"e015212","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Frailty of older patients is not reflected in the melanoma tumor microenvironment and treatment response to immune checkpoint blockade therapy"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6729-9479","authenticated-orcid":false,"given":"Asli","family":"\u00d6zkan","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8195-736X","authenticated-orcid":false,"given":"Marieke","family":"IJsselsteijn","sequence":"additional","affiliation":[{"name":"Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9079-0293","authenticated-orcid":false,"given":"Ziena","family":"Abdulrahman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"van der Ploeg","sequence":"additional","affiliation":[{"name":"Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4814-6426","authenticated-orcid":false,"given":"Ellen","family":"Kapiteijn","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marije","family":"Slingerland","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4449-8707","authenticated-orcid":false,"given":"Els M E","family":"Verdegaal","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marij J P","family":"Welters","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sjoerd H","family":"van der Burg","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanneke E A","family":"Portielje","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6122-1024","authenticated-orcid":false,"given":"Noel F C C","family":"de Miranda","sequence":"additional","affiliation":[{"name":"Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nienke A","family":"de Glas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Helse F\u00f8rde, F\u00f8rde, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"2026091806200999000_14.9.e015212.1","doi-asserted-by":"crossref","DOI":"10.3390\/vaccines11091412","article-title":"Efficacy and safety of vaccinations in geriatric patients: a literature review","volume":"11","author":"Ciarambino","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"2026091806200999000_14.9.e015212.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2005.08.105"},{"key":"2026091806200999000_14.9.e015212.3","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/S0140-6736(12)62167-9","article-title":"Frailty in elderly people","volume":"381","author":"Clegg","year":"2013","journal-title":"The Lancet"},{"key":"2026091806200999000_14.9.e015212.4","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s12603-023-1885-1","article-title":"Frailty reduces vaccine effectiveness against SARS-CoV-2 infection: a test-negative case control study using national VA data","volume":"27","author":"Tang","year":"2023","journal-title":"J Nutr Health Aging"},{"key":"2026091806200999000_14.9.e015212.5","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13112826","article-title":"Toxicity, response and survival in older patients with metastatic melanoma treated with checkpoint inhibitors","volume":"13","author":"de Glas","year":"2021","journal-title":"Cancers (Basel)"},{"key":"2026091806200999000_14.9.e015212.6","doi-asserted-by":"crossref","first-page":"115056","DOI":"10.1016\/j.ejca.2024.115056","article-title":"Adjuvant immunotherapy in older patients with stage III and resected stage IV melanoma: Toxicity and recurrence-free survival outcomes from the Dutch melanoma treatment registry","volume":"212","author":"\u00d6zkan","year":"2024","journal-title":"Eur J Cancer"},{"key":"2026091806200999000_14.9.e015212.7","doi-asserted-by":"crossref","DOI":"10.1186\/s40425-018-0336-8","article-title":"Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis","volume":"6","author":"Elias","year":"2018","journal-title":"J Immunother Cancer"},{"key":"2026091806200999000_14.9.e015212.8","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1002\/ijc.70185","article-title":"Impact of geriatric impairments on outcomes of single-agent immunotherapy in solid tumors","volume":"158","author":"\u00d6zkan","year":"2026","journal-title":"Int J Cancer"},{"key":"2026091806200999000_14.9.e015212.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836"},{"key":"2026091806200999000_14.9.e015212.10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-3146"},{"key":"2026091806200999000_14.9.e015212.11","doi-asserted-by":"publisher","DOI":"10.1016\/J.CCELL.2019.01.003"},{"key":"2026091806200999000_14.9.e015212.12","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4466"},{"key":"2026091806200999000_14.9.e015212.13","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.cpt.2023.08.001","article-title":"Impact of immunosenescence and inflammaging on the effects of immune checkpoint inhibitors","volume":"2","author":"Hou","year":"2024","journal-title":"Cancer Pathog Ther"},{"key":"2026091806200999000_14.9.e015212.14","article-title":"Immunotherapy: should we worry about immunosenescence?","volume":"1","author":"\u00d6zkan","year":"2024","journal-title":"Ageing Cancer Res Treat"},{"key":"2026091806200999000_14.9.e015212.15","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.abi5072","article-title":"Spatially mapping the immune landscape of melanoma using imaging mass cytometry","volume":"7","author":"Moldoveanu","year":"2022","journal-title":"Sci Immunol"},{"key":"2026091806200999000_14.9.e015212.16","doi-asserted-by":"publisher","DOI":"10.5770\/cgj.23.463"},{"key":"2026091806200999000_14.9.e015212.17","doi-asserted-by":"crossref","first-page":"505","DOI":"10.2147\/CIA.S365494","article-title":"Frailty and cancer: current perspectives on assessment and monitoring","volume":"18","author":"Goede","year":"2023","journal-title":"Clin Interv Aging"},{"key":"2026091806200999000_14.9.e015212.18","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s00392-020-01792-w","article-title":"Effect of frailty on treatment, hospitalisation and death in patients with chronic heart failure","volume":"110","author":"Sze","year":"2021","journal-title":"Clin Res Cardiol"},{"key":"2026091806200999000_14.9.e015212.19","doi-asserted-by":"crossref","DOI":"10.1186\/s12979-024-00463-y","article-title":"Blood based immune biomarkers associated with clinical frailty scale in older patients with melanoma receiving checkpoint inhibitor immunotherapy","volume":"21","author":"Tran Van Hoi","year":"2024","journal-title":"Immun Ageing"},{"key":"2026091806200999000_14.9.e015212.20","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.02534","article-title":"A 40-marker panel for high dimensional characterization of cancer immune microenvironments by imaging mass cytometry","volume":"10","author":"Ijsselsteijn","year":"2019","journal-title":"Front Immunol"},{"key":"2026091806200999000_14.9.e015212.21","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/bs.mcb.2024.10.014","article-title":"Multidimensional profiling of cancer microenvironments in FFPE tissues by imaging mass cytometry","volume":"191","author":"Ijsselsteijn","year":"2025","journal-title":"Methods Cell Biol"},{"key":"2026091806200999000_14.9.e015212.22","doi-asserted-by":"crossref","first-page":"3920","DOI":"10.1016\/j.csbj.2024.10.048","article-title":"PENGUIN: a rapid and efficient image preprocessing tool for multiplexed spatial proteomics","volume":"23","author":"Sequeira","year":"2024","journal-title":"Comput Struct Biotechnol J"},{"key":"2026091806200999000_14.9.e015212.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01094-0"},{"key":"2026091806200999000_14.9.e015212.24","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22625"},{"key":"2026091806200999000_14.9.e015212.25","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.00933"},{"key":"2026091806200999000_14.9.e015212.26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00502"},{"key":"2026091806200999000_14.9.e015212.27","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160168"},{"key":"2026091806200999000_14.9.e015212.28","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1116"},{"key":"2026091806200999000_14.9.e015212.29","doi-asserted-by":"crossref","DOI":"10.3390\/cells12010044","article-title":"Association between Immunosenescence, Mitochondrial Dysfunction and Frailty Syndrome in Older Adults","volume":"12","author":"Buondonno","year":"2022","journal-title":"Cells"},{"key":"2026091806200999000_14.9.e015212.30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.11.7446"},{"key":"2026091806200999000_14.9.e015212.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0373-7"},{"key":"2026091806200999000_14.9.e015212.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00684-4"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2026-015212","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T13:20:18Z","timestamp":1789737618000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2026-015212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":32,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,18]]},"published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1136\/jitc-2026-015212"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2026-015212","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]}}}