{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:16:49Z","timestamp":1790194609488,"version":"4.1.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010623","name":"University of Thessaly","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010623","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005187","name":"National and Kapodistrian University of Athens","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005187","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The spatial distribution and functional heterogeneity of tumor-infiltrating lymphocytes (TILs) significantly impact patient outcomes in non-small cell lung cancer (NSCLC). While T cell factor 1 (TCF1) expressing TILs have emerged as key players in sustaining anti-tumor immunity, their subset characterization, localization, and clinical significance within the tumor microenvironment remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      We performed multiplex immunohistochemistry and immunofluorescence to characterize TCF1\n                      <jats:sup>+<\/jats:sup>\n                      immune cell subsets, in 102 NSCLC tumors, separately analyzing the tumor center (TC) and invasive front (IF). We integrated this data with publicly available single-cell RNA-sequencing datasets and clinical outcome analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and CD79\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      B cells, dominate the TCF1\n                      <jats:sup>+<\/jats:sup>\n                      landscape, while CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells constitute a minority of TCF1\n                      <jats:sup>+<\/jats:sup>\n                      immune cells, particularly in the TC. We demonstrated the presence of tumor-infiltrating IgG\n                      <jats:sup>+<\/jats:sup>\n                      \/IgA\n                      <jats:sup>+<\/jats:sup>\n                      plasma cells co-expressing TCF1. PD1\n                      <jats:sup>+<\/jats:sup>\n                      TCF1\n                      <jats:sup>-<\/jats:sup>\n                      cells were more frequent than PD1\n                      <jats:sup>+<\/jats:sup>\n                      TCF1\n                      <jats:sup>+<\/jats:sup>\n                      cells both in the TC and IF, reflecting that terminally differentiated exhausted TILs predominate within the tumor microenvironment. Survival analyses revealed significantly different prognostic impact of TILs including TCF1-expressing cells based on topography. Multivariate analysis showed that increased CD8\n                      <jats:sup>+<\/jats:sup>\n                      TCF1\n                      <jats:sup>+<\/jats:sup>\n                      cells (HR: 2.5; p=0.039) and increased TCF1 expression by cancer cells (HR: 2,7; p=0.041) in the TC and CD4\n                      <jats:sup>+<\/jats:sup>\n                      TCF1\n                      <jats:sup>+<\/jats:sup>\n                      cells (HR: 0.4; p=0.043) in the IF emerged as negative and positive independent prognostic markers for Disease-free survival (DFS), respectively. Integrating PD-L1 expression with TILs, PD-L1 immunopositivity was correlated with increased CD8\n                      <jats:sup>+<\/jats:sup>\n                      and PD1\n                      <jats:sup>+<\/jats:sup>\n                      TCF1\n                      <jats:sup>-<\/jats:sup>\n                      cell infiltration and was associated with favorable DFS especially in the TC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings support a more refined framework for TCF1\n                      <jats:sup>+<\/jats:sup>\n                      TIL assessment and TCF1 expression across cellular populations in the tumor microenvironment, with implications for prognostication in operable NSCLC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1731337","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T06:56:06Z","timestamp":1769064966000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Immunophenotyping TCF1-expressing TILs: spatial profiling and prognostic value in operable non-small cell lung cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Konstantinos","family":"Ntostoglou","sequence":"first","affiliation":[{"name":"Hellenic Oncology Research Group (HORG)","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Christodoulopoulos","sequence":"additional","affiliation":[{"name":"Laboratory of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly","place":["Larissa, Greece"]},{"name":"Department of Medical Oncology, University General Hospital of Larissa","place":["Larissa, 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