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Fero","doi-asserted-by":"publisher","award":["BBASELGAFERO2024.01"],"award-info":[{"award-number":["BBASELGAFERO2024.01"]}],"id":[{"id":"10.13039\/501100018779","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008061","name":"Fundacion Mutua Madrile\u00f1a","doi-asserted-by":"crossref","award":["AP18051-2022"],"award-info":[{"award-number":["AP18051-2022"]}],"id":[{"id":"10.13039\/100008061","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,8,24]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors have transformed non-small cell lung cancer (NSCLC) treatment. Understanding the tumor-immune interactions that dictate sensitivity to PD-1 blockade is essential for improving outcomes and optimizing immunotherapy personalization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed compartment-specific (tumor\/immune) spatial proteomic profiling (GeoMx) on a discovery cohort of 104 patients with advanced, PD-L1-high (tumor proportion score \u226550%) NSCLC treated with first-line pembrolizumab. Identified markers were further assessed using orthogonal methods in two independent early-stage NSCLC cohorts treated with neoadjuvant\/perioperative chemo-immunotherapy: (a) NADIM trial (n=36) with bulk RNA-seq and (b) NeoITX_H12O cohort (N=41) with quantitative immunohistochemistry. Potential baseline prognostic value without immunotherapy was evaluated in the TCGA dataset (N=940). Functional validation was assessed using in vitro and in vivo (nude and syngeneic) models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified tumor-cell OX40L, but not immune-cell OX40L, as the single marker significantly associated with prolonged progression-free survival (PFS) and overall survival under single-agent pembrolizumab in patients with PD-L1-high tumors. Spatially resolved analysis linked tumor-intrinsic OX40L to an active immune microenvironment with increased antigen presentation. In both neoadjuvant\/perioperative cohorts, high OX40L levels in residual tumors from patients with non-pathological complete response were associated with superior PFS. Conversely, no significant association with survival was observed in the immunotherapy-na\u00efve TCGA cohort. Functional studies confirmed that OX40L-expressing NSCLC cells directly co-stimulate T cells in vitro and significantly enhance anti-PD-1 efficacy in vivo (p=0.0005), without affecting intrinsic tumor growth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>OX40L expressed by tumor cells contributes to an enhanced efficacy of PD-1 blockade in patients with NSCLC. These findings may open new therapeutic avenues and potentially contribute to improving immunotherapy personalization in this disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-016133","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T08:30:22Z","timestamp":1789201822000},"page":"e016133","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor cell-expressed OX40L enhances the efficacy of PD-1 axis blockade in non-small cell lung cancer"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct03081689","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Carmen","family":"Fern\u00e1ndez-Luna","sequence":"first","affiliation":[{"name":"Tumor Microenvironment and Precision Oncology Research Group, Instituto de Investigaci\u00f3n Hospital 12 de Octubre (i+12), Madrid, Community of Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Baena","sequence":"additional","affiliation":[{"name":"Tumor Microenvironment and Precision Oncology Research Group, Instituto de Investigaci\u00f3n Hospital 12 de Octubre (i+12), Madrid, Community of Madrid, Spain"},{"name":"Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Calles","sequence":"additional","affiliation":[{"name":"Hospital General Universitario Gregorio Mara\u00f1\u00f3n, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Anto\u00f1anzas-Basa","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Lage 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Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer. N Engl J Med 2025;741\u201352. doi:10.1056\/NEJMOA2502931\/SUPPL_FILE\/NEJMOA2502931_DATA-SHARING.PDF","DOI":"10.1056\/NEJMoa2502931"},{"key":"2026091201301621000_14.9.e016133.3","doi-asserted-by":"crossref","first-page":"S1607","DOI":"10.1016\/j.annonc.2025.09.079","article-title":"LBA67 Perioperative pembrolizumab in early-stage non-small- cell lung cancer (NSCLC): 5-year follow-up from KEYNOTE- 671","volume":"36","author":"Wakelee","year":"2025","journal-title":"Annals of Oncology"},{"key":"2026091201301621000_14.9.e016133.4","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1538"},{"key":"2026091201301621000_14.9.e016133.5","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy218"},{"key":"2026091201301621000_14.9.e016133.6","doi-asserted-by":"crossref","unstructured":"Majem M , Cobo M , Isla D , et al . Pd-(L)1 inhibitors as monotherapy for the first-line treatment of non-small-cell lung cancer patients with high pd-l1 expression: A network meta-analysis. 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