{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:42:07Z","timestamp":1791859327954,"version":"4.3.4"},"reference-count":54,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"unspecified","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,11,17]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Compared with conventional chemotherapy, pembrolizumab-based chemoimmunotherapy (Pembro) and nivolumab plus ipilimumab with or without two cycles of platinum-doublet chemotherapy (Nivo+Ipi) improve survival in advanced non-small cell lung cancer (NSCLC). However, biomarkers for selecting optimal immunotherapy remain unclear. This study aimed to assess whether programmed cell death-ligand 1 (PD-L1) expression on tumor and immune cells (ICs) can guide first-line immunotherapy in advanced NSCLC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This multicenter, observational study retrospectively reviewed patients with NSCLC treated with first-line Pembro or Nivo+Ipi\u2009who had evaluable PD-L1 expression on tumor (Tumor Proportion Score (TPS), 22C3) and ICs score (SP142). In addition, whole-exome and RNA sequencing were performed on treatment-na\u00efve NSCLCs with available PD-L1 expression status by both assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Between 2019 and 2023, 198 patients were included (Pembro\/Nivo+Ipi: 137\/61). In the Pembro cohort, patients with high TPS (\u2265 50%) had significantly longer progression-free survival (PFS) than those with low TPS (&lt; 50%) (median PFS (mPFS, months): 8.1 vs 7.1; p=0.02), while IC score was not predictive. In the Nivo+Ipi cohort, high IC score (\u22651) was associated with longer PFS than low IC score (0) (mPFS: 7.7 vs 2.8; p=0.04), while TPS showed no impact. Among patients with low TPS\/high IC scores, Nivo+Ipi achieved longer PFS than Pembro (mPFS: 12.4 vs 6.6; restricted mean survival time (RMST)\n                      <jats:sub>Nivo+Ipi<\/jats:sub>\n                      \/RMST\n                      <jats:sub>Pembro<\/jats:sub>\n                      (24 months)=1.5; p=0.049). Multiomics analysis using 152 NSCLC samples showed that tumors with low TPS\/high IC scores exhibited an activated tumor immune microenvironment comparable to that of tumors with high TPS. However, these tumors had significantly highest tumor mutation burden (TMB) and regulatory T cell (T\n                      <jats:sub>reg<\/jats:sub>\n                      ) fraction among the PD-L1 phenotypes (median TMB (mut\/Mb): 1.6 in tumors with low TPS\/low IC score, 18.2 in low TPS\/high IC score, and 1.9 in high TPS\/any IC score; median T\n                      <jats:sub>reg<\/jats:sub>\n                      fraction (\u00d710\n                      <jats:sup>\u22122<\/jats:sup>\n                      ]: 0.0, 0.2, and 0.0, respectively), supporting a potential benefit of cytotoxic T-lymphocyte-associated antigen 4 blockade in addition to programmed cell death protein 1 (PD-1)\/PD-L1 inhibition in this subgroup.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Patients with NSCLC and low TPS\/high IC scores may benefit more from Nivo+Ipi than from Pembro due to distinct genomic and immunological features, including high TMB and T\n                      <jats:sub>reg<\/jats:sub>\n                      fraction.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012880","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T09:50:33Z","timestamp":1764928233000},"page":"e012880","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["PD-L1 phenotype classification based on expression in tumor and immune cells as a potential biomarker for optimizing anti-PD-1\/CTLA-4 immunotherapies in NSCLC"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9229-2276","authenticated-orcid":false,"given":"Jun","family":"Miyakoshi","sequence":"first","affiliation":[{"name":"Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, 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