{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:54:48Z","timestamp":1792637688472,"version":"4.5.0"},"reference-count":44,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"unspecified","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1093017"],"award-info":[{"award-number":["APP1093017"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,5,4]]},"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Adjuvant immune checkpoint inhibitor (ICI) immunotherapies have significantly reduced the recurrence rate in high-risk patients with stage III melanoma compared with surgery alone. However, 48% of anti-PD-1-treated patients will develop recurrent disease within 4 years. There is a need to identify biomarkers of recurrence after adjuvant ICI to enable identification of patients in need of alternative treatment strategies. As cytotoxic T cells are critical for the antitumor response to anti-PD-1, we sought to determine whether specific subsets were predictive of recurrence in anti-PD-1-treated high-risk patients with stage III melanoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Associations with recurrence in patients with stage III melanoma were sought by analyzing resection specimens (n=103) taken prior to adjuvant nivolumab\/pembrolizumab\u00b1low-dose\/low-interval ipilimumab. Multiplex immunohistochemistry was used to quantify intratumoral CD8+ T-cell populations using phenotypical markers CD39, CD103, and PD-1.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>With a median follow-up of 19.3 months, 37\/103 (36%) of patients had a recurrence. Two CD8+ T-cell subpopulations were significantly associated with recurrence. First, CD39+ tumor-resident memory cells (CD39+CD103+PD-1+CD8+ (CD39+ Trm)) comprised a significantly higher proportion of CD8+ T cells in recurrence-free patients (p=0.0004). Conversely, bystander T cells (CD39\u2212CD103\u2212PD-1\u2212CD8+) comprised a significantly greater proportion of T cells in patients who developed recurrence (p=0.0002). Spatial analysis identified that CD39+ Trms localized significantly closer to melanoma cells than bystander T cells. Multivariable analysis confirmed significantly improved recurrence-free survival (RFS) in patients with a high proportion of intratumoral CD39+ Trms (1-year RFS high 78.1% vs low 49.9%, HR 0.32, 95% CI 0.15 to 0.69), no complete lymph node dissection performed, and less advanced disease stage (HR 2.85, 95% CI 1.13 to 7.19, and HR 1.29, 95% CI 0.59 to 2.82). The final Cox regression model identified patients who developed recurrence with an area under the curve of 75.9% in the discovery cohort and 69.5% in a separate validation cohort (n=33) to predict recurrence status at 1\u2009year.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Adjuvant immunotherapy-treated patients with a high proportion of CD39+ Trms in their baseline melanoma resection have a significantly reduced risk of melanoma recurrence. This population of T cells may not only represent a biomarker of RFS following anti-PD-1 therapy, but may also be an avenue for therapeutic manipulation and enhancing outcomes for immunotherapy-treated patients with cancer.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-004771","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T12:38:21Z","timestamp":1654864701000},"page":"e004771","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Higher proportions of CD39+ tumor-resident cytotoxic T cells predict recurrence-free survival in patients with stage III melanoma treated with adjuvant immunotherapy"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8926-6582","authenticated-orcid":false,"given":"Grace Heloise","family":"Attrill","sequence":"first","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina N","family":"Owen","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"The University of Bristol, Bristol Cancer Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasnia","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismael A","family":"Vergara","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J","family":"Colebatch","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Department of Tissue Oncology and Diagnostic Pathology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan W","family":"Conway","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazi J","family":"Nahar","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2816-2496","authenticated-orcid":false,"given":"John F","family":"Thompson","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital; Mater Hospital, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3540-8906","authenticated-orcid":false,"given":"Ines","family":"Pires da Silva","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo S","family":"Carlino","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M","family":"Menzies","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5092-5544","authenticated-orcid":false,"given":"Serigne","family":"Lo","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1113-3306","authenticated-orcid":false,"given":"Umaimainthan","family":"Palendira","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8991-0013","authenticated-orcid":false,"given":"Richard A","family":"Scolyer","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Department of Tissue Oncology and Diagnostic Pathology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8894-3545","authenticated-orcid":false,"given":"Georgina V","family":"Long","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-5244","authenticated-orcid":false,"given":"James S","family":"Wilmott","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,6,10]]},"reference":[{"key":"2025100304073218000_10.6.e004771.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1802357"},{"key":"2025100304073218000_10.6.e004771.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709030"},{"key":"2025100304073218000_10.6.e004771.3","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1200\/JCO.20.02110","article-title":"Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: updated results from the EORTC 1325-MG\/KEYNOTE-054 trial","volume":"38","author":"Eggermont","year":"2020","journal-title":"J Clin Oncol"},{"key":"2025100304073218000_10.6.e004771.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611299"},{"key":"2025100304073218000_10.6.e004771.5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejca.2019.07.001","article-title":"Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European organisation for research and treatment of cancer 18071 double-blind phase 3 randomised trial","volume":"119","author":"Eggermont","year":"2019","journal-title":"Eur J Cancer"},{"key":"2025100304073218000_10.6.e004771.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-01188-3"},{"key":"2025100304073218000_10.6.e004771.7","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/s41591-020-01211-7","article-title":"Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma","volume":"27","author":"Rozeman","year":"2021","journal-title":"Nat Med"},{"key":"2025100304073218000_10.6.e004771.8","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/S0140-6736(20)30417-7","article-title":"Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial","volume":"395","author":"Zimmer","year":"2020","journal-title":"Lancet"},{"key":"2025100304073218000_10.6.e004771.9","doi-asserted-by":"crossref","unstructured":"Long GV , Schadendorf D , Del Vecchio M . Adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (PTS) with resected stage IIIB-D\/IV melanoma (Checkmate 915). In American association of cancer research (AACR) annual meeting 2021.","DOI":"10.1158\/1538-7445.AM2021-CT004"},{"key":"2025100304073218000_10.6.e004771.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31601-X"},{"key":"2025100304073218000_10.6.e004771.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709684"},{"key":"2025100304073218000_10.6.e004771.12","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30494-0"},{"key":"2025100304073218000_10.6.e004771.13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-3218"},{"key":"2025100304073218000_10.6.e004771.14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200690"},{"key":"2025100304073218000_10.6.e004771.15","doi-asserted-by":"crossref","DOI":"10.1093\/annonc\/mdw379.07","article-title":"PD-L1 expression as a biomarker for nivolumab (NIVO) plus ipilimumab (IPI) and NIVO alone in advanced melanoma (MEL): a pooled analysis","volume":"27","author":"Long","year":"2016","journal-title":"Ann Oncol"},{"key":"2025100304073218000_10.6.e004771.16","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1200\/JCO.2016.67.2477","article-title":"Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma","volume":"34","author":"Daud","year":"2016","journal-title":"J Clin Oncol"},{"key":"2025100304073218000_10.6.e004771.17","doi-asserted-by":"publisher","DOI":"10.1111\/pcmr.12340"},{"key":"2025100304073218000_10.6.e004771.18","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/S0140-6736(21)01206-X","article-title":"Immune checkpoint inhibitors in melanoma","volume":"398","author":"Carlino","year":"2021","journal-title":"Lancet"},{"key":"2025100304073218000_10.6.e004771.19","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1680"},{"key":"2025100304073218000_10.6.e004771.20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836"},{"key":"2025100304073218000_10.6.e004771.21","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2019.37.15_suppl.9511","article-title":"Comprehensive molecular profiling of metastatic melanoma to predict response to monotherapy and combination immunotherapy","volume":"37","author":"Pires Da Silva","year":"2019","journal-title":"J Clin Oncol"},{"key":"2025100304073218000_10.6.e004771.22","doi-asserted-by":"publisher","DOI":"10.1016\/J.CCELL.2019.01.003"},{"key":"2025100304073218000_10.6.e004771.23","doi-asserted-by":"publisher","DOI":"10.1038\/nature13954"},{"key":"2025100304073218000_10.6.e004771.24","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2257"},{"key":"2025100304073218000_10.6.e004771.25","doi-asserted-by":"publisher","DOI":"10.1038\/nature19330"},{"key":"2025100304073218000_10.6.e004771.26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500515"},{"key":"2025100304073218000_10.6.e004771.27","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002231"},{"key":"2025100304073218000_10.6.e004771.28","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053214"},{"key":"2025100304073218000_10.6.e004771.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0130-2"},{"key":"2025100304073218000_10.6.e004771.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05072-0"},{"key":"2025100304073218000_10.6.e004771.31","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41586-021-03704-y","article-title":"Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma","volume":"596","author":"Oliveira","year":"2021","journal-title":"Nature"},{"key":"2025100304073218000_10.6.e004771.32","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e31826485c0"},{"key":"2025100304073218000_10.6.e004771.33","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.pathol.2020.10.007","article-title":"Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumours: a guide to immunohistochemistry implementation and interpretation","volume":"53","author":"Paver","year":"2021","journal-title":"Pathology"},{"key":"2025100304073218000_10.6.e004771.34","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/s43018-020-0038-2","article-title":"Bystander IFN-\u03b3 activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment","volume":"1","author":"Thibaut","year":"2020","journal-title":"Nat Cancer"},{"key":"2025100304073218000_10.6.e004771.35","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-020-0036-4"},{"key":"2025100304073218000_10.6.e004771.36","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2019.1659093","article-title":"Close proximity of immune and tumor cells underlies response to anti-PD-1 based therapies in metastatic melanoma patients","volume":"9","author":"Gide","year":"2020","journal-title":"Oncoimmunology"},{"key":"2025100304073218000_10.6.e004771.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0812-9"},{"key":"2025100304073218000_10.6.e004771.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0522-3"},{"key":"2025100304073218000_10.6.e004771.39","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2018.11.043","article-title":"Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma","volume":"176","author":"Li","year":"2019","journal-title":"Cell"},{"key":"2025100304073218000_10.6.e004771.40","doi-asserted-by":"publisher","DOI":"10.1038\/nature18945"},{"key":"2025100304073218000_10.6.e004771.41","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb9847"},{"key":"2025100304073218000_10.6.e004771.42","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1708539"},{"key":"2025100304073218000_10.6.e004771.43","doi-asserted-by":"crossref","first-page":"e378","DOI":"10.1016\/S1470-2045(19)30332-8","article-title":"Neoadjuvant systemic therapy in melanoma: recommendations of the International neoadjuvant melanoma Consortium","volume":"20","author":"Amaria","year":"2019","journal-title":"Lancet Oncol"},{"key":"2025100304073218000_10.6.e004771.44","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-4011"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2022-004771","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T11:07:41Z","timestamp":1759489661000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2022-004771"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6,10]]},"published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1136\/jitc-2022-004771"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2022-004771","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6]]}}}