{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:41:50Z","timestamp":1793727710134,"version":"4.6.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"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                      HLA-G is a non-classical major histocompatibility complex class I molecule with potent immunosuppressive activity and is increasingly recognized as an immune-checkpoint axis in cancer. Its prognostic significance in non-small cell lung cancer (NSCLC), particularly in relation to PD-L1 expression and CD8\n                      <jats:sup>+<\/jats:sup>\n                      tumor-infiltrating lymphocytes (TILs), remains incompletely defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We retrospectively analyzed 314 surgically resected NSCLCs assembled in tissue microarrays and stained for HLA-G, PD-L1, and CD8. HLA-G and PD-L1 were scored as positive when \u22651% of tumor cells showed membranous staining, whereas CD8\n                      <jats:sup>+<\/jats:sup>\n                      TIL density was digitally quantified and dichotomized using the cohort median (\u2265575 cells\/mm\u00b2). Associations with clinicopathological variables and outcomes were assessed by Kaplan\u2013Meier analysis and multivariable Cox regression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HLA-G was expressed in 50 of 314 tumors (16%), PD-L1 in 106 of 314 (33.8%), and high CD8 density in 160 of 314 (51%). In HLA-G-negative tumors, high CD8\n                      <jats:sup>+<\/jats:sup>\n                      TIL density was associated with significantly prolonged disease-free survival (DFS) and overall survival (OS). In the overall cohort, the combined HLA-G-negative\/CD8-high phenotype retained independent favorable prognostic significance for both DFS and OS. By contrast, CD8 density did not significantly stratify outcome in HLA-G-positive tumors, although these subgroup analyses were limited by small sample size.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      In combined biomarker analyses, the favorable prognostic effect of CD8\n                      <jats:sup>+<\/jats:sup>\n                      TILs in PD-L1-negative tumors was maintained only when HLA-G was also absent. Within the PD-L1-positive\/HLA-G-negative subgroup, high CD8 density was independently associated with improved DFS but not OS. Integrating HLA-G with PD-L1 and CD8 assessment may refine prognostic stratification and help identify patients who could benefit from HLA-G-targeted strategies, alone or in combination with PD-1\/PD-L1 blockade.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1732852","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T05:45:23Z","timestamp":1781243123000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["HLA-G expression in non-small cell lung cancer: prognostic significance and interplay with PD-L1 and CD8+ tumor-infiltrating lymphocytes"],"prefix":"10.3389","volume":"17","author":[{"given":"Giulia","family":"Querzoli","sequence":"first","affiliation":[{"name":"Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna","place":["Bologna, 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IRCCS","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisella","family":"Righi","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Oncology, University of Torino at San Luigi Hospital","place":["Orbassano, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Pilotto","sequence":"additional","affiliation":[{"name":"Department of Engineering for Innovation Medicine (DIMI), University of Verona and Verona University Hospital Trust","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Cali\u00f2","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Public Health, Section of Pathology, University of Verona and Verona University Hospital Trust","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Cima","sequence":"additional","affiliation":[{"name":"Pathology Unit, Verona University Hospital Trust","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Gobbo","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Public Health, Section of Pathology, University of Verona and Verona University Hospital Trust","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Cecchini","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University","place":["London, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Paolino","sequence":"additional","affiliation":[{"name":"Pathology Unit, ASST Spedali Civili di Brescia","place":["Brescia, 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