Xu Yituo, Huang Zhijie, Yu Xingjuan, Li Zhixiong, Zheng Limin, Xu Jing
Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
Biologics. 2021 Aug 13;15:329-341. doi: 10.2147/BTT.S325019. eCollection 2021.
Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a member of the B7 family; however, little is known regarding its expression and clinical relevance in hepatocellular carcinoma (HCC).
To better characterize HHLA2 expression in HCC, we analyzed its expression by in situ staining and further investigated its correlation with immune infiltration and patient prognosis.
HHLA2 was primarily expressed in the peri-tumor region of HCC tissues and co-localized with CD68 monocytes/macrophages. In vitro analysis and multi-immunofluorescence staining showed up-regulated HHLA2 expression in tumor-activated monocytes/macrophages, and HHLA2 monocytes/macrophages expressed high levels of HLA-DR in HCC tissue. A correlation analysis showed that samples displaying high HHLA2 expression in the peri-tumor region had significant tumor infiltration of CD204 and CD11b cells, and low expression of genes associated with an anti-tumor immune response. The high level of peri-tumoral HHLA2 expression was associated with a poor patient overall survival (OS; = 0.008). A multivariate analysis revealed that HHLA2 expression in the peri-tumor region was an independent prognostic factor for OS (hazard ratio = 1.872, = 0.003). Moreover, the expression of HHLA2 was negatively correlated with PD-L1, and patients exhibiting HHLA2 and programmed cell death-ligand 1(PD-L1) co-expression had the shortest survival time.
HHLA2 expression represented an immunosuppressive microenvironment in HCC, and may serve as a potential target for immunotherapy.
人类内源性逆转录病毒-H长末端重复序列相关蛋白2（HHLA2）是B7家族的成员；然而，关于其在肝细胞癌（HCC）中的表达及临床相关性知之甚少。
为了更好地表征HHLA2在HCC中的表达，我们通过原位染色分析其表达，并进一步研究其与免疫浸润和患者预后的相关性。
HHLA2主要在HCC组织的肿瘤周边区域表达，并与CD68单核细胞/巨噬细胞共定位。体外分析和多重免疫荧光染色显示，肿瘤激活的单核细胞/巨噬细胞中HHLA2表达上调，且HHLA2单核细胞/巨噬细胞在HCC组织中表达高水平的HLA-DR。相关性分析表明，肿瘤周边区域HHLA2高表达的样本中CD204和CD11b细胞有显著的肿瘤浸润，且与抗肿瘤免疫反应相关的基因表达较低。肿瘤周边HHLA2高表达与患者总生存期（OS）较差相关（P = 0.008）。多变量分析显示，肿瘤周边区域的HHLA2表达是OS的独立预后因素（风险比 = 1.872，P = 0.003）。此外，HHLA2的表达与程序性死亡受体配体1（PD-L1）呈负相关，HHLA2和PD-L1共表达的患者生存时间最短。
HHLA2表达代表了HCC中的免疫抑制微环境，可能作为免疫治疗的潜在靶点。
