Expression of HHLA2 in hepatocellular carcinoma tissues and its clinical significance / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression of human endogenous retrovirus subfamily H long terminal repeat associating protein 2 (HHLA2) in hepatocellular carcinoma (HCC) tissues and its correlation with the clinicopathological characteristics and prognosis of patients with HCC. Methods: Based on TCGA database, the correlation between HHLA2 mRNA expression and B7 family genes in human HCC tissues was analyzed. HHLA2 expression in 90 pairs of HCC tissues and their adjacent tissues was detected by tissue microarry and immunohistochemical staining. Wilcoxon rank sum test was used to compare the difference of HHLA2 expression between HCC tissues and its adjacent tissues. The chi-square test was used to analyze the relationship between HHLA2 expression in human HCC tissues and clinicopathological features of the patients. Kaplan-Meier survival analysis was performed to analyze the correlation between HHLA2 expression and patients’ overall survival (OS), and the Cox model was used to evaluate the prognostic value of different indices. Results: The expression level of HHLA2 mRNA in HCC tissues was correlated with B7 family CD274, C10orf54, PDCD1LG2, ICOSLG and CD276. The expression level of HHLA2 in HCC tissues was significantly correlated with tumor size (χ2=4.531, P<0.05). The OS of HCC patients with high HHLA2 expression was significantly shorter than that of the patients with lower HHLA2 expression (HR=1.878, 95%CI: 1.066-3.309, P<0.05). The COX model showed that tumor size (HR=2.493, 95%CI: 1.310-4.742, P<0.01) could be used as an independent risk factor for the prognostic prediction of the patients. Conclusion: HHLA2 is significantly correlated with the prognosis of HCC patients, and can be used as a potential target for HCC immunotherapy.

Research progress of HHLA2/TMIGD2 in solid tumors / 中国肿瘤生物治疗杂志

@#以程序性死亡因子 1（PD-1）及其配体 1（PD-L1）为代表的B7/CD28家族在肿瘤免疫治疗中显示出极大的应用潜力，但仍 有很多PD-L1检测阴性患者无法从中受益。作为B7家族成员，人内源性逆转录病毒-H长末端重复关联蛋白2 (HHLA2)分子结 构与PD-L1等其他B7家族成员有一定的同源性和相似性， 对T细胞有共刺激和共抑制作用，在多数实体肿瘤中呈高表达，且在某 些实体肿瘤中表达比PD-L1更广泛；其通过与受体穿膜和免疫球蛋白结构域2(TMIGD2)结合可促进肿瘤免疫逃逸，导致肿瘤的 进展和转移。基于此，HHLA2/TMIGD2有望成为肿瘤免疫治疗新的通路和靶点之一。本文就HHLA2及其受体TMIGD2的分子 结构、生物学功能及其在实体肿瘤中作用的研究进展作一综述。

Expression and clinical significance of HERV-HLTR-associating protein 2 in hepatocellular carcinoma / 重庆医学

Objective To investigate the expression of HERV-HLTR-associating protein 2(HHLA2).in hepatocellular carcinoma(HCC) tissue and its relationship with different pathological grades,clinical stages,liver function and serum AFP level.Methods The positive rate of HHLA2 expression in 150 cases of paraffin-embedded HCC tissues was detected by immunohistochemistry.Ten cases of normal liver tissue specimens from health donors served as the normal control.The differences of HHLA2 expression in HCC tissues were compared among different pathological grades,clinical stage,liver function grades and serum AFP levels.Results The positive expression rate of HHLA2 in HCC tissue was significantly higher than that in normal control (P＜0.05).The positive rate of HHLA2 expression in low differentiated HCC tissue was highest.The positive rate of HHLA2 expression in the low differentiation and moderate differentiation HCC groups was significantly higher than that in the high differentiation group (P＜0.05).The positive expression rate in the patients with Barcelona stage C and D was significantly higher than that in the patients with the stage A and B(P＜0.05).The positive expression rate in the patients with Child-Pugh stage A was significantly higher than that in the patients with stage B and C(P＜0.01).While the HHLA2 expression rate had no statistically significant difference among different ages and different serum AFP levels(P＞0.05).Conclusion The positive expression rate of HHLA2 in cancer tissues of HCC patients is significantly increased.HHLA2 might play a certain role in the occurrence,development and metastasis of HCC.

Research progress of new mumber HHLA2 of B7 family / 中国免疫学杂志

HHLA2 is a newly discovered B7 family member.HHLA2 appears to have limited expression in normal tissues.TMIGD,one of the receptors HHLA2 is established.Similar to HHLA2,TMIGD2 is absent in mouse and rat while it is found in human and higher primates.HHLA2 with inhibition of CD4 and CD8 T cell proliferation,but also can inhibit the role of T cells secrete some cytokines.HHLA2 protein is absent in most normal tissues,but mainly expressed on epithelial cells of a few tissues.But HHLA2 is widely expressed in various human cancers such as lung cancer,breast cancer and osteosarcoma et al,that make HHLA2 might be a new target for human cancers immunotherapy.

Research progress of HHLA2 in malignant tumor / 中国免疫学杂志

With in-depth study on tumor pathogenesis in recent years,immunotherapy has gained breakthroughs,and Pembrolizumab,Nivolumab and other drugs,which are represented by programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1),have been approved for clinical use.Both human endogenous retrovirus subfamily H long terminal repeat associating protein 2 (HHLA2) and PD-L1 belong to B7 family and are homologous.They are highly expressed in various solid malignant tumors and are very likely to be another significant immunoassay and therapeutic target in succession to PD-L1.Research progress of HHLA2 in malignant tumors will be reviewed.