{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:43:51Z","timestamp":1785908631065,"version":"3.56.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      High neutrophil-lymphocyte ratio (NLR) and neutrophil extracellular traps (NETs) are associated with poor overall survival in many cancers but are currently remain without safe effective therapy until subtype elucidation identifies a targetable molecular subtype whose inhibition will not compromise homeostatic pathogen defense. We tested the hypothesis that increased circulating NET-forming neutrophils (NET\n                      <jats:sup>+<\/jats:sup>\n                      Ns) expressing the cell-surface dual endothelin-1\/signal receptor (DEspR) comprise a subtype that predicts poor survival outcomes in patients with metastatic non-small cell lung cancer (mNSCLC) receiving first-line chemotherapy-immunotherapy (chemo-IO), because peripheral levels of DEspR\n                      <jats:sup>+<\/jats:sup>\n                      neutrophils and NET\n                      <jats:sup>+<\/jats:sup>\n                      Ns are increased in neutrophil-mediated secondary tissue injury during sterile inflammation across different diseases in which high NLR is associated with disease progression or exacerbation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In a prospective observational study, we subtyped neutrophils by flow cytometry and NET\n                      <jats:sup>+<\/jats:sup>\n                      Ns by immunofluorescence cytology (IFC) confocal microscopy using fresh whole blood samples from 10 patients with mNSCLC at baseline and 6 weeks after the first dose of chemo-IO. We performed Kaplan\u2013Meier survival analysis and Cox regression with Firth\u2019s penalty for 2-year overall survival (OS) and restricted mean survival time (RMST) analyses for 1-year OS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In 10 patients with mNSCLC, immunosuppressive PDL1\n                      <jats:sup>+<\/jats:sup>\n                      DEspR\n                      <jats:sup>+<\/jats:sup>\n                      neutrophils and monocytes were increased at pretreatment baseline compared with normal levels. IFC detected increased circulating DEspR\n                      <jats:sup>+<\/jats:sup>\n                      citH3\n                      <jats:sup>+<\/jats:sup>\n                      [NET\n                      <jats:sup>+<\/jats:sup>\n                      Ns] and microvesicles (MVs), the majority of which were also PDL1\n                      <jats:sup>+<\/jats:sup>\n                      , and persisted 6 weeks after the first dose of chemo-IO. IFC of buffy coat smears detected DEspR\n                      <jats:sup>+<\/jats:sup>\n                      [NET\n                      <jats:sup>+<\/jats:sup>\n                      Ns] complexed with DEspR\n                      <jats:sup>+<\/jats:sup>\n                      EpCAM\n                      <jats:sup>+<\/jats:sup>\n                      circulating tumor cells (CTCs). Concordant findings from Kaplan-Meier survival analysis and univariate Cox regression with Firth's penalty for 2-year overall survival (OS), and RMST for 1-year OS identified significant association between high baseline levels of DEspR+[NET+N] subtpe and overall survival respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These data identify the DEspR\n                      <jats:sup>+<\/jats:sup>\n                      subtype of citH3\n                      <jats:sup>+<\/jats:sup>\n                      \/PDL1\n                      <jats:sup>+<\/jats:sup>\n                      [NET\n                      <jats:sup>+<\/jats:sup>\n                      Ns] and MVs whose respective levels correlate with decreased 1-year and 2-year OS in patients with mNSCLC receiving first-line chemo-IO. Visualization of NET\n                      <jats:sup>+<\/jats:sup>\n                      N intercellular complexes in circulation depicts ongoing systemic inflammatory-immunosuppressive microenvironment in mNSCLC. As DEspR is cell-surface accessible and targetable, these data collectively provide a basis for further confirmatory research to evaluate DEspR as a potential actionable biomarker in larger and independent mNSCLC cohorts.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1849858","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:45:42Z","timestamp":1785905142000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Prospective subtyping identifies an association between high pretreatment levels of DEspR+ neutrophil extracellular trap\u2013forming neutrophils and microvesicles during sterile inflammation with poor survival in patients with metastatic non-small cell lung cancer receiving first-line combination chemo-immunotherapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Victoria L. 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