The association of HHLA2 and PD-L1 expression with prognosis and immune microenvironment in hepatocellular carcinoma

Abstract

Abstract Background HHLA2, a newly discovered B7 family member, is widely expressed in numerous tumors and regulates the immune microenvironment. However, its prognostic value remains controversial, and the roles of HHLA2 in hepatocellular carcinoma (HCC) are unclear. In this study, we aimed to investigate the expression patterns of HHLA2 and PD-L1 in HCC and elaborate their relationship with TILs (tumor-infiltrating lymphocytes) and the prognosis of patients with HCC. Methods HHLA2 and PD-L1 expression were evaluated through immunohistochemistry (IHC) and analyzed in relation to clinicopathological characteristics in cancer tissues from HCC cases (n = 547). When membranous or cytoplasmatic expression of PD-L1 > = 1% was considered a positive expression. The percentage (%) and quantification (per mm2) of TILs were evaluated by hematoxylin and eosin staining (HE). The quantification of CD3+, CD4 + and CD8 + TILs (per mm2) was evaluated by IHC. Results The positive rates of HHLA2 were comparable with those of PD-L1 in HCC tissues according to immunohistochemistry score. HHLA2-positive expression was significantly associated with old age, low serum AFP level and well tumor differentiation, and indicated a better overall survival (OS). Besides, HHLA2 expression was significantly associated with a low density of stromal TILs. However, PD-L1 expression on TC (Tumor cells) was significantly associated with a high density of stromal TILs, CD3 + and CD8 + TILs, similarly, PD-L1 expression on IC (Inflammatory cells) were also correlated with high density of stromal TILs, CD3+, CD4 + and CD8 + TILs. Notably, a new immune classification, based on HHLA2/PD-L1, successfully stratified OS, and patients with HHLA2(+)/PD-L1(-) status had the longest survival. Conclusion HHLA2 has a critical impact on the immune microenvironment and can be used as an independent prognostic factor for HCC. Combined the expression of HHLA2 and PD-L1 can be used as a new classification to stratify the risk of progression and death for patients with HCC. Our study may provide evidence for improving responses to immunotherapy-included comprehensive treatment for HCC in the future.