Frontiers in immunology · 2026
HLA-G expression in non-small cell lung cancer: prognostic significance and interplay with PD-L1 and CD8+ tumor-infiltrating lymphocytes.
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Querzoli Giulia, Bogina Giuseppe, Marconi Marcella, Tumino Nicola, Vacca Paola, Righi Luisella, Pilotto Sara, Caliò Anna, Cima Luca, Gobbo Stefano, Cecchini Matthew J, Paolino Gaetano, Ciompi Francesco, Accolla Roberto S, Scarpa Aldo, Lunardi Gianluigi, Marcenaro Emanuela, Moretta Lorenzo, Zamboni Giuseppe, Munari Enrico
Аннотация
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.
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.