Introduction: 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+ tumor-infiltrating lymphocytes (TILs), remains incompletely defined. Methods: 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 ≥1% of tumor cells showed membranous staining, whereas CD8+ TIL density was digitally quantified and dichotomized using the cohort median (≥575 cells/mm²). Associations with clinicopathological variables and outcomes were assessed by Kaplan-Meier analysis and multivariable Cox regression. Results: 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+ 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. Discussion: In combined biomarker analyses, the favorable prognostic effect of CD8+ 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.
HLA-G expression in non-small cell lung cancer: prognostic significance and interplay with PD-L1 and CD8+ tumor-infiltrating lymphocytes
Pilotto, Sara;Caliò, Anna;Cima, Luca;Gobbo, Stefano;Scarpa, Aldo;Zamboni, Giuseppe;Munari, Enrico
2026-01-01
Abstract
Introduction: 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+ tumor-infiltrating lymphocytes (TILs), remains incompletely defined. Methods: 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 ≥1% of tumor cells showed membranous staining, whereas CD8+ TIL density was digitally quantified and dichotomized using the cohort median (≥575 cells/mm²). Associations with clinicopathological variables and outcomes were assessed by Kaplan-Meier analysis and multivariable Cox regression. Results: 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+ 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. Discussion: In combined biomarker analyses, the favorable prognostic effect of CD8+ 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.
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