{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:42:04Z","timestamp":1792503724197,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2023MH065"],"award-info":[{"award-number":["ZR2023MH065"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin & Trans Imm"],"published-print":{"date-parts":[[2026,10]]},"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n Extensive\u2010stage small cell lung cancer (ES\u2010SCLC) remains an aggressive malignancy with limited durable responses to immune checkpoint inhibitors (ICIs) and no established predictive biomarkers. This study aimed to evaluate the prognostic and predictive value of tertiary lymphoid structures (TLSs) in patients with ES\u2010SCLC receiving ICI\u2010based therapy.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n In this multicenter retrospective study of 180 treatment\u2010na\u00efve ES\u2010SCLC patients subsequently receiving ICI\u2010based therapy, TLSs were systematically evaluated using H&E staining, multiplex immunofluorescence, and spatial analysis to determine their prognostic and predictive value.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n TLSs were identified in 22.2% of cases and independently associated with improved overall survival (OS) in both univariate (HR\u2009=\u20090.365, 95% CI: 0.217\u20130.613,\n P<\/jats:italic>\n \u2009<\u20090.001) and multivariate (HR\u2009=\u20090.337, 95% CI: 0.199\u20130.569,\n P<\/jats:italic>\n \u2009<\u20090.001) analyses. Crucially, TLS maturation status was associated with clinical outcomes, as patients with mature TLSs containing CD21\n +<\/jats:sup>\n follicular dendritic cells and organized germinal centers experienced significantly longer survival than those with non\u2010mature TLSs (\n P<\/jats:italic>\n \u2009=\u20090.0049). Beyond mere presence, responders to ICIs exhibited distinct spatial characteristics, including higher TLS densities, denser immune infiltration, and shorter distances between TLS\u2010resident CD20\n +<\/jats:sup>\n B cells, CD3\n +<\/jats:sup>\n T\u00a0cells, and tumor cells, suggesting that immune\u2013tumor spatial organization within TLSs reflects functional antitumor engagement.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n TLS maturation and spatial architecture may serve as candidate tissue biomarkers associated with clinical outcomes in ICI\u2010treated ES\u2010SCLC, warranting prospective validation alongside SCLC molecular subtyping.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/cti2.70125","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:10:39Z","timestamp":1792501839000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial and maturational characterisation of tertiary lymphoid structures predicts immunotherapy response in extensive\u2010stage small cell lung cancer"],"prefix":"10.1002","volume":"15","author":[{"given":"Haoyu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine\u2010Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenglong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9648-8869","authenticated-orcid":false,"given":"Zhenxiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chufeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinhao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamao","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4732-9972","authenticated-orcid":false,"given":"Haiyong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"620","article-title":"Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions","volume":"73","author":"Megyesfalvi Z","year":"2023","journal-title":"CA Cancer J Clin"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1001\/jama.2025.0560","article-title":"Small cell lung cancer: A review","volume":"333","author":"Kim SY","year":"2025","journal-title":"JAMA"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13045-025-01690-6","article-title":"Current and future therapies for small cell lung carcinoma","volume":"18","author":"Zhai X","year":"2025","journal-title":"J Hematol Oncol"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1016\/S0140-6736(19)32222-6","article-title":"Durvalumab plus platinum\u2010etoposide versus platinum\u2010etoposide in first\u2010line treatment of extensive\u2010stage small\u2010cell lung cancer (CASPIAN): A randomised, controlled, open\u2010label, phase 3 trial","volume":"394","author":"Paz\u2010Ares L","year":"2019","journal-title":"Lancet"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.annonc.2019.10.021","article-title":"Safety and patient\u2010reported outcomes of atezolizumab, carboplatin, and etoposide in extensive\u2010stage small\u2010cell lung cancer (IMpower133): A randomized phase I\/III trial","volume":"31","author":"Mansfield AS","year":"2020","journal-title":"Ann Oncol"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1200\/JCO.20.01055","article-title":"Updated overall survival and PD\u2010L1 subgroup analysis of patients with extensive\u2010stage small\u2010cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133)","volume":"39","author":"Liu SV","year":"2021","journal-title":"J Clin Oncol"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40425-016-0153-x","article-title":"PD\u2010L1 biomarker testing for non\u2010small cell lung cancer: Truth or fiction?","volume":"4","author":"Grigg C","year":"2016","journal-title":"J Immunother Cancer"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1056\/NEJMoa1801946","article-title":"Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden","volume":"378","author":"Hellmann MD","year":"2018","journal-title":"N Engl J Med"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1001\/jamaoncol.2022.4933","article-title":"Association of machine learning\u2010based assessment of tumor\u2010infiltrating lymphocytes on standard histologic images with outcomes of immunotherapy in patients with NSCLC","volume":"9","author":"Rakaee M","year":"2023","journal-title":"JAMA Oncol"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/s41568-024-00728-0","article-title":"Tertiary lymphoid structures in anticancer immunity","volume":"24","author":"Teillaud JL","year":"2024","journal-title":"Nat Rev Cancer"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41586-019-1914-8","article-title":"Tertiary lymphoid structures improve immunotherapy and survival in melanoma","volume":"577","author":"Cabrita R","year":"2020","journal-title":"Nature"},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/s41586-019-1922-8","article-title":"B cells and tertiary lymphoid structures promote immunotherapy response","volume":"577","author":"Helmink BA","year":"2020","journal-title":"Nature"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-024-52153-4","article-title":"Single\u2010cell and spatial transcriptome analyses reveal tertiary lymphoid structures linked to tumour progression and immunotherapy response in nasopharyngeal carcinoma","volume":"15","author":"Liu Y","year":"2024","journal-title":"Nat Commun"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13046-025-03318-6","article-title":"Multiple mechanisms and applications of tertiary lymphoid structures and immune checkpoint blockade","volume":"44","author":"Li Z","year":"2025","journal-title":"J Exp Clin Cancer Res"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"605","DOI":"10.7150\/thno.105423","article-title":"B cells and tertiary lymphoid structures in tumors: Immunity cycle, clinical impact, and therapeutic applications","volume":"15","author":"Wu X","year":"2025","journal-title":"Theranostics"},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"4410","DOI":"10.1200\/JCO.2007.15.0284","article-title":"Long\u2010term survival for patients with non\u2010small\u2010cell lung cancer with intratumoral lymphoid structures","volume":"26","author":"Dieu\u2010Nosjean MC","year":"2008","journal-title":"J Clin Oncol"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1164\/rccm.201309-1611OC","article-title":"Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer","volume":"189","author":"Germain C","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-29040-x","article-title":"Tertiary lymphoid structures critical for prognosis in endometrial cancer patients","volume":"13","author":"Horeweg N","year":"2022","journal-title":"Nat Commun"},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"9459","DOI":"10.7150\/thno.113940","article-title":"Dissecting tertiary lymphoid structures in cancer: Maturation, localization and density","volume":"15","author":"Su GL","year":"2025","journal-title":"Theranostics"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s13045-025-01754-7","article-title":"Tertiary lymphoid structures in cancer: Spatiotemporal heterogeneity, immune orchestration, and translational opportunities","volume":"18","author":"Deng S","year":"2025","journal-title":"J Hematol Oncol"},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1001\/jama.2022.16464","article-title":"Effect of first\u2010line serplulimab vs placebo added to chemotherapy on survival in patients with extensive\u2010stage small cell lung cancer: The ASTRUM\u2010005 randomized clinical trial","volume":"328","author":"Cheng Y","year":"2022","journal-title":"JAMA"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/S1470-2045(22)00224-8","article-title":"Adebrelimab or placebo plus carboplatin and etoposide as first\u2010line treatment for extensive\u2010stage small\u2010cell lung cancer (CAPSTONE\u20101): A multicentre, randomised, double\u2010blind, placebo\u2010controlled, phase 3 trial","volume":"23","author":"Wang J","year":"2022","journal-title":"Lancet Oncol"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s13578-024-01283-9","article-title":"Advances in predictive biomarkers associated with immunotherapy in extensive\u2010stage small cell lung cancer","volume":"14","author":"Chen T","year":"2024","journal-title":"Cell Biosci"},{"key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1007\/s00432-023-05544-x","article-title":"Predictive biomarkers for immunotherapy response in extensive\u2010stage SCLC","volume":"150","author":"Zhu L","year":"2024","journal-title":"J Cancer Res Clin Oncol"},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.xcrm.2025.101934","article-title":"Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with mature tertiary lymphoid structures","volume":"6","author":"Peyraud F","year":"2025","journal-title":"Cell Rep Med"},{"key":"e_1_2_10_27_1","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-005531","article-title":"Maturation and abundance of tertiary lymphoid structures are associated with the efficacy of neoadjuvant chemoimmunotherapy in resectable non\u2010small cell lung cancer","volume":"10","author":"Sun X","year":"2022","journal-title":"J Immunother Cancer"},{"key":"e_1_2_10_28_1","doi-asserted-by":"crossref","DOI":"10.1172\/JCI181517","article-title":"ACAT1 regulates tertiary lymphoid structures and correlates with immunotherapy response in non\u2010small cell lung cancer","volume":"135","author":"Jiao M","year":"2025","journal-title":"J Clin Invest"},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.jhep.2021.10.030","article-title":"Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma","volume":"76","author":"Ding GY","year":"2022","journal-title":"J Hepatol"},{"key":"e_1_2_10_30_1","doi-asserted-by":"crossref","DOI":"10.1126\/science.abf9419","article-title":"Tertiary lymphoid structures in cancer","volume":"375","author":"Schumacher TN","year":"2022","journal-title":"Science"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary lymphoid structures in the era of cancer\u00a0immunotherapy","volume":"19","author":"Saut\u00e8s\u2010Fridman C","year":"2019","journal-title":"Nat Rev Cancer"},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.medj.2024.10.023","article-title":"Tertiary lymphoid structures and cancer immunotherapy: From bench to bedside","volume":"6","author":"Peyraud F","year":"2025","journal-title":"Med"},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/s41571-022-00619-z","article-title":"B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome","volume":"19","author":"Fridman WH","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"e_1_2_10_34_1","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1016\/j.immuni.2023.08.009","article-title":"Tertiary lymphoid structures and B cells: An intratumoral immunity cycle","volume":"56","author":"Fridman WH","year":"2023","journal-title":"Immunity"},{"key":"e_1_2_10_35_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2024.105003","article-title":"Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancer","volume":"101","author":"Di Modugno F","year":"2024","journal-title":"EBioMedicine"},{"key":"e_1_2_10_36_1","doi-asserted-by":"crossref","DOI":"10.1002\/mco2.461","article-title":"Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma","volume":"5","author":"Xu W","year":"2024","journal-title":"MedComm (2020)"},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-009243","article-title":"Mapping the complexity and diversity of tertiary lymphoid structures in primary and peritoneal metastatic gastric cancer","volume":"12","author":"Groen\u2010van Schooten TS","year":"2024","journal-title":"J Immunother Cancer"},{"key":"e_1_2_10_38_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13046-025-03341-7","article-title":"Single\u2010cell transcriptomics analysis reveals that the tumor\u2010infiltrating B cells determine the indolent fate of papillary thyroid carcinoma","volume":"44","author":"Li C","year":"2025","journal-title":"J Exp Clin Cancer Res"},{"key":"e_1_2_10_39_1","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.ccell.2020.12.014","article-title":"Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities","volume":"39","author":"Gay CM","year":"2021","journal-title":"Cancer Cell"},{"key":"e_1_2_10_40_1","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.semcancer.2022.04.001","article-title":"Small cell lung cancer: Subtypes and therapeutic implications","volume":"86","author":"Wang WZ","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"e_1_2_10_41_1","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202402716","article-title":"Spatial transcriptome\u2010wide profiling of small cell lung cancer reveals intra\u2010Tumoral molecular and subtype heterogeneity","volume":"11","author":"Zhang Z","year":"2024","journal-title":"Adv Sci (Weinh)"}],"container-title":["Clinical & Translational Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cti2.70125","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cti2.70125","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cti2.70125","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:10:44Z","timestamp":1792501844000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cti2.70125"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/cti2.70125"],"URL":"https:\/\/doi.org\/10.1002\/cti2.70125","archive":["Portico"],"relation":{},"ISSN":["2050-0068","2050-0068"],"issn-type":[{"value":"2050-0068","type":"print"},{"value":"2050-0068","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-06-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70125"}}