Luo Min, Lin Yan, Liang Rong, Li Yongqiang, Ge Lianying
Department of Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, People's Republic of China.
Department of Endoscopy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, People's Republic of China.
J Inflamm Res. 2021 Aug 28;14:4217-4228. doi: 10.2147/JIR.S324336. eCollection 2021.
The protein "human endogenous retrovirus H long terminal repeat-associating 2" (HHLA2), a member of the B7 family, has been linked to cancer progression and immune responses. However, its functional role in hepatocellular carcinoma (HCC) remains unknown.
Bioinformatics was used to examine the potential roles of HHLA2 in HCC and the molecular pathways involved. Expression of HHLA2 and PD-L1 as well as the density of tumor-infiltrating lymphocytes (TILs) in tumoral areas were evaluated by immunohistochemistry and hematoxylin-eosin staining of 202 resected human HCC samples. Potential correlations of HHLA2 expression with pathological characteristics or prognosis of HCC patients were explored. Different types of immune microenvironment in HCC were defined based on HHLA2 expression and TIL density.
High HHLA2 levels in HCC correlated with more advanced clinical cancer stage ( = 0.040), multiple tumors ( = 0.044), poor tumor differentiation ( = 0.048), microvascular invasion ( = 0.011) and hepatic capsule invasion ( = 0.047). HHLA2 levels correlated significantly with density of TILs, but not with PD-L1 levels. High HHLA2 levels were associated with worse prognosis. Intermediate and high TIL densities were independent predictors of better prognosis. Tumor microenvironments with type I (HHLA2 - high TILs +) or type IV (HHLA2 - low TILs +) were associated with better prognosis.
HHLA2 level can independently predict worse prognosis and affect the tumor microenvironment in HCC, which may help guide immunotherapy against the cancer.
蛋白质“人类内源性逆转录病毒H长末端重复序列关联蛋白2”（HHLA2）是B7家族成员，与癌症进展和免疫反应有关。然而，其在肝细胞癌（HCC）中的功能作用尚不清楚。
采用生物信息学方法研究HHLA2在HCC中的潜在作用及相关分子途径。通过对202例切除的人类HCC样本进行免疫组织化学和苏木精-伊红染色，评估HHLA2和PD-L1的表达以及肿瘤区域肿瘤浸润淋巴细胞（TILs）的密度。探讨HHLA2表达与HCC患者病理特征或预后的潜在相关性。基于HHLA2表达和TIL密度定义HCC中不同类型的免疫微环境。
HCC中HHLA2高水平与更晚期的临床癌症分期（P = 0.040）、多发肿瘤（P = 0.044）、肿瘤低分化（P = 0.048）、微血管侵犯（P = 0.011）和肝包膜侵犯（P = 0.047）相关。HHLA2水平与TILs密度显著相关，但与PD-L1水平无关。HHLA2高水平与较差的预后相关。中等和高TIL密度是较好预后的独立预测因素。I型（HHLA2高TILs +）或IV型（HHLA2低TILs +）肿瘤微环境与较好的预后相关。
HHLA2水平可独立预测较差的预后并影响HCC的肿瘤微环境，这可能有助于指导针对该癌症的免疫治疗。
