Distinct Roles of HHLA2 and PD-L1 in the Immune Cell and Prognosis of Hepatocellular Carcinoma

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Background: HHLA2, a member of the B7 family, is extensively expressed in various cancers and plays a pivotal role in modulating the immune microenvironment. However, its prognostic significance in hepatocellular carcinoma (HCC) remains poorly understood. This study aims to elucidate the expression patterns of HHLA2 and PD-L1 in HCC, their associations with tumor-infiltrating lymphocytes (TILs), and their impact on clinical outcomes. Methods: Immunohistochemistry (IHC) was employed to evaluate HHLA2 and PD-L1 expression in 547 HCC tissue samples. PD-L1 positivity was defined as ≥1% membranous or cytoplasmic staining. Hematoxylin and eosin (H&E) staining was utilized to quantify TILs (percentage/area), while IHC was used to measure the densities of CD3+, CD4+, and CD8+ TILs (cells/mm²). Results: HHLA2 and PD-L1 exhibited similar positivity rates. HHLA2 positivity was associated with older age, lower alpha-fetoprotein (AFP) levels, well-differentiated tumors, and improved overall survival (OS). HHLA2 expression was inversely correlated with stromal TIL density. In contrast, tumor cell (TC)-PD-L1 and inflammatory cell (IC)-PD-L1 positivity were positively correlated with higher stromal TIL density and increased levels of CD3+, CD4+, and CD8+ TILs. Patients with HHLA2(+)/PD-L1(-) status demonstrated the longest OS. A novel classification system based on HHLA2/PD-L1 expression identified distinct immune profiles and prognostic subgroups. Conclusion: HHLA2 significantly influences the immune microenvironment of HCC and serves as an independent prognostic marker. The combined assessment of HHLA2 and PD-L1 expression facilitates risk stratification, providing a framework to optimize immunotherapy strategies. These findings contribute to the advancement of precision medicine in the management of HCC.

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