{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T17:11:30Z","timestamp":1783789890253,"version":"3.55.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"content-version":"vor","delay-in-days":10,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Anti\u2013PD-1 monotherapy has shown a significant survival benefit for patients with advanced-stage melanoma. In this study, we explored whether long-term clinical benefit is determined by abundance or changes in such abundances of CD4 and CD8 T-cell subsets in blood. Peripheral blood mononuclear cells from 58 patients with advanced-stage melanoma treated with anti\u2013PD-1 monotherapy were collected prior to first, second, and third administration. Overall survival (OS) was categorized into 3 groups: &amp;lt;1\u2009yr (short term); 1\u20133\u2009yr; and &amp;gt;3\u2009yr (long term). The abundance of different T-cell subsets was determined via multiplex flow cytometry and transcriptomics analysis. Long- and short-term survivors demonstrated no differences in frequencies of CD4 and CD8 T-cell subsets at baseline. However, on-treatment, long-term survivors showed an early increase in the frequency of CD4 T cells expressing 4-1BB, whereas this subset frequency was decreased in short-term survivors. Notably, this early increase in the 4-1BB+ CD4 T-cell frequency was associated with an increase in the frequency of LAG3+TIM3+ CD4 T cells and followed by a later decrease in the frequency of FOXP3+ CD4 T cells. Notably, 4-1BB+ CD4 T cells of long-term survivors demonstrated a distinctively high expression of IL-17. In short, long-term survivors have unique on-treatment changes in the frequency of different CD4 T-cell subsets, particularly those related to co-signaling and regulatory T cells. These results show that CD4 T cell\u2013mediated stimulation and differentiation are associated with long-term benefit of anti\u2013PD-1 treatment, which may guide development of future treatment strategies.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag171","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T16:12:26Z","timestamp":1783786346000},"source":"Crossref","is-referenced-by-count":0,"title":["Long-term survivors of melanoma after anti\u2013PD-1 therapy demonstrate on-treatment increase in abundance of 4-1BB+ CD4 T cells in blood"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5928-2899","authenticated-orcid":false,"given":"Karlijn","family":"de Joode","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayri E","family":"Balcioglu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"van Brakel","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda T","family":"L\u00f3pez-Cascales","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan P","family":"Hurkmans","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin A","family":"Basak","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Oomen-de Hoop","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cor H","family":"Lamers","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim G","family":"Aerts","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron H","family":"Mathijssen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid A M","family":"van der Veldt","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]},{"name":"Department of Radiology & Nuclear Medicine, Erasmus MC Cancer Institute, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reno","family":"Debets","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC 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