HLA-G expression in non-small cell lung cancer: prognostic significance and interplay with PD-L1 and CD8+ tumor-infiltrating lymphocytes

IntroductionHLA-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.MethodsWe 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.

ResultsHLA-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.