{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T11:21:18Z","timestamp":1787743278980,"version":"build-2784847793"},"reference-count":49,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"unspecified","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH","award":["R01CA290027"],"award-info":[{"award-number":["R01CA290027"]}]},{"name":"NIH","award":["R01DE032033"],"award-info":[{"award-number":["R01DE032033"]}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["BR2278\/8-1"],"award-info":[{"award-number":["BR2278\/8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["TRR332\/project A4"],"award-info":[{"award-number":["TRR332\/project A4"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"F.Hoffmann-La Roche Ltd","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100004337","name":"F. Hoffmann-La Roche Ltd","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100004337","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,31]]},"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neoadjuvant immunotherapy has emerged as a promising strategy for patients with head and neck squamous cell carcinoma. However, the systemic immune mechanisms underlying treatment response remain insufficiently defined. This study evaluated the clinical feasibility and immunological effects of a single neoadjuvant dose of a programmed death-ligand 1 (PD-L1) blocking antibody in patients with resectable head and neck squamous cell carcinoma, with a particular focus on immune cell dynamics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this phase II, open-label, non-randomized window-of-opportunity study (PIONEER trial,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04939480\">NCT04939480<\/jats:ext-link>\n                      ), patients received one dose of the PD-L1-targeting antibody atezolizumab before surgery. Clinical safety, operability, and pathological response were assessed. A translational research program incorporated intensive immune monitoring based on immediate processing of freshly collected peripheral blood samples, enabling reliable quantification of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which are highly sensitive to freeze-thaw procedures. Additional immune profiling was performed to track treatment-induced systemic immune activation and cytokine dynamics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All patients proceeded to surgery without delay, and neoadjuvant atezolizumab was well tolerated. Pathological tumor regression exceeding 50% was observed in 7 of 20\u2009patients (35%), including 5\u2009patients with major pathological response. Treatment induced a transient peak in type II interferon-associated cytokines and defined signatures of cell-mediated immunity approximately 15 days after antibody administration. Patients who achieved robust pathological regression displayed higher baseline frequencies of activated natural killer T cells and exhausted T cells, with further expansion after treatment. Importantly, immediate blood processing revealed that pronounced tumor regression was consistently associated with an early and marked reduction in mature immunosuppressive PMN-MDSC\u2014a finding that would have been obscured by conventional frozen sample workflows.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A single neoadjuvant dose of atezolizumab was feasible, safe, and elicited measurable systemic immune activation in patients with resectable head and neck squamous cell carcinoma. Direct analysis of fresh blood uncovered dynamic PMN-MDSC changes as a potential novel pharmacodynamic biomarker of treatment response, emphasizing the advantages of real-time, non-frozen immune cell profiling for complete assessment of immune cell dynamics in neoadjuvant immunotherapy studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04939480\">NCT04939480<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015762","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T10:45:21Z","timestamp":1787741121000},"page":"e015762","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Pre-existing systemic immune state and dynamic myeloid remodeling shape response to neoadjuvant PD-L1 blockade"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct04939480","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04939480","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04939480","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Stefan","family":"Kasper","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, University Hospital Essen, Essen, Germany"},{"name":"German Cancer Consortium, DKTK, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1435-5195","authenticated-orcid":false,"given":"Hendrik","family":"Winkel","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"H\u00f6ing","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Bruderek","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Pogorzelski","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Deuss","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga","family":"Gr\u00fcnewald","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospital M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Doreth","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5161-5254","authenticated-orcid":false,"given":"Xi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Theurer","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","family":"Arakawa-Hoyt","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology -Head and Neck Surgery, Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohini","family":"Maitra","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology -Head and Neck Surgery, Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Guberina","sequence":"additional","affiliation":[{"name":"German Cancer Consortium, DKTK, Heidelberg, Germany"},{"name":"Department of Radiotherapy, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Virchow","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital Essen, Essen, Germany"},{"name":"National Center for Tumor Diseases (NCT), NCT West, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schuler","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital Essen, Essen, Germany"},{"name":"National Center for Tumor Diseases (NCT), NCT West, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew H","family":"Spitzer","sequence":"additional","affiliation":[{"name":"Depts. of Otolaryngology-Head and Neck Surgery and of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius H","family":"K\u00fcrten","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2702-4163","authenticated-orcid":false,"given":"Sven","family":"Brandau","sequence":"additional","affiliation":[{"name":"German Cancer Consortium, DKTK, Heidelberg, Germany"},{"name":"Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"2026082603451459000_14.8.e015762.1","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1056\/NEJMoa2408154","article-title":"Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer","volume":"391","author":"Powles","year":"2024","journal-title":"N Engl J Med"},{"key":"2026082603451459000_14.8.e015762.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1802357"},{"key":"2026082603451459000_14.8.e015762.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2302983"},{"key":"2026082603451459000_14.8.e015762.4","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-31941-w","article-title":"Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC","volume":"13","author":"Saddawi-Konefka","year":"2022","journal-title":"Nat Commun"},{"key":"2026082603451459000_14.8.e015762.5","doi-asserted-by":"crossref","DOI":"10.1126\/science.aax0182","article-title":"Neoadjuvant checkpoint blockade for cancer immunotherapy","volume":"367","author":"Topalian","year":"2020","journal-title":"Science"},{"key":"2026082603451459000_14.8.e015762.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.07.012"},{"key":"2026082603451459000_14.8.e015762.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.07.011"},{"key":"2026082603451459000_14.8.e015762.8","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-024-46450-1","article-title":"Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors","volume":"15","author":"Gil-Jimenez","year":"2024","journal-title":"Nat Commun"},{"key":"2026082603451459000_14.8.e015762.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03752-4"},{"key":"2026082603451459000_14.8.e015762.10","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1001\/jamaoto.2025.0410","article-title":"Neoadjuvant Therapy for Mucosal Head and Neck Squamous Cell Carcinoma: A Review From the American Head and Neck Society","volume":"151","author":"Contrera","year":"2025","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"2026082603451459000_14.8.e015762.11","doi-asserted-by":"crossref","DOI":"10.1186\/s12943-025-02487-4","article-title":"Neoadjuvant immunotherapy in squamous cell carcinoma of the head and neck: current evidence and future perspectives","volume":"24","author":"Zhang","year":"2025","journal-title":"Mol Cancer"},{"key":"2026082603451459000_14.8.e015762.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2415434"},{"key":"2026082603451459000_14.8.e015762.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-024-00969-w"},{"key":"2026082603451459000_14.8.e015762.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.02.026"},{"key":"2026082603451459000_14.8.e015762.15","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.adf4968","article-title":"Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer","volume":"8","author":"Oliveira","year":"2023","journal-title":"Sci Immunol"},{"key":"2026082603451459000_14.8.e015762.16","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-0585"},{"key":"2026082603451459000_14.8.e015762.17","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-1695"},{"key":"2026082603451459000_14.8.e015762.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00705-7"},{"key":"2026082603451459000_14.8.e015762.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.02.021"},{"key":"2026082603451459000_14.8.e015762.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.022"},{"key":"2026082603451459000_14.8.e015762.21","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-0939"},{"key":"2026082603451459000_14.8.e015762.22","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1158\/1078-0432.CCR-23-3249","article-title":"A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma","volume":"30","author":"Kim","year":"2024","journal-title":"Clinical Cancer Research"},{"key":"2026082603451459000_14.8.e015762.23","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1158\/1078-0432.CCR-21-1816","article-title":"Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma","volume":"28","author":"Luginbuhl","year":"2022","journal-title":"Clinical Cancer Research"},{"key":"2026082603451459000_14.8.e015762.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.018"},{"key":"2026082603451459000_14.8.e015762.25","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-009278","article-title":"Circulating T cell status and molecular imaging may predict clinical benefit of neoadjuvant PD-1 blockade in oral cancer","volume":"12","author":"Wondergem","year":"2024","journal-title":"J Immunother Cancer"},{"key":"2026082603451459000_14.8.e015762.26","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3726"},{"key":"2026082603451459000_14.8.e015762.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00347-z"},{"key":"2026082603451459000_14.8.e015762.28","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy218"},{"key":"2026082603451459000_14.8.e015762.29","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-1-0716-1060-2_5","article-title":"Isolation of Human Circulating Myeloid-Derived Suppressor Cells and Analysis of Their Immunosuppressive Activity","volume":"2236","author":"Bruderek","year":"2021","journal-title":"Methods Mol Biol"},{"key":"2026082603451459000_14.8.e015762.30","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-001223","article-title":"Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation","volume":"8","author":"Cassetta","year":"2020","journal-title":"J Immunother Cancer"},{"key":"2026082603451459000_14.8.e015762.31","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2019.05.046"},{"key":"2026082603451459000_14.8.e015762.32","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.020"},{"key":"2026082603451459000_14.8.e015762.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00556-8"},{"key":"2026082603451459000_14.8.e015762.34","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms12150","article-title":"Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards","volume":"7","author":"Bronte","year":"2016","journal-title":"Nat Commun"},{"key":"2026082603451459000_14.8.e015762.35","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-04-713206"},{"key":"2026082603451459000_14.8.e015762.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01311-1"},{"key":"2026082603451459000_14.8.e015762.37","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"2026082603451459000_14.8.e015762.38","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2021-002568","article-title":"Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial","volume":"9","author":"Ferris","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2026082603451459000_14.8.e015762.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2020.102966"},{"key":"2026082603451459000_14.8.e015762.40","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081398"},{"key":"2026082603451459000_14.8.e015762.41","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003080"},{"key":"2026082603451459000_14.8.e015762.42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803648"},{"key":"2026082603451459000_14.8.e015762.43","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-010-0963-5"},{"key":"2026082603451459000_14.8.e015762.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.12.005"},{"key":"2026082603451459000_14.8.e015762.45","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-002242","article-title":"Neutrophils in the era of immune checkpoint blockade","volume":"9","author":"Faget","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2026082603451459000_14.8.e015762.46","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19656"},{"key":"2026082603451459000_14.8.e015762.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.04.007"},{"key":"2026082603451459000_14.8.e015762.48","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-10-119636"},{"key":"2026082603451459000_14.8.e015762.49","doi-asserted-by":"crossref","DOI":"10.1128\/MMBR.00057-17","article-title":"The Ontogeny of a Neutrophil: Mechanisms of Granulopoiesis and Homeostasis","volume":"82","author":"Lawrence","year":"2018","journal-title":"Microbiol Mol Biol Rev"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2026-015762","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T10:45:27Z","timestamp":1787741127000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2026-015762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":49,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,26]]},"published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1136\/jitc-2026-015762"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2026-015762","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]}}}