Han Wenzheng, Lv Jinrong, Wang Mintuo, Wu Xiaoxin, Sun Dongdong, Chen Wenwen, Wang Yingying, Zhou Wenjie, Yang Yuxuan, Bao Jia, Han Qingzhen, Chen Xiaopeng, Guo Fei, Feng Gang, Li Min, Chen Qing
The First Affiliated Hospital, Wannan Medical College, Anhui, China.
Institute of Biology and Medical Sciences, Soochow University, Jiangsu, China.
Balkan Med J. 2025 May 5;42(3):242-253. doi: 10.4274/balkanmedj.galenos.2025.2025-1-129.
Targeted therapies directed at tumor immune checkpoint, like programmed death-ligand (PD-L)1/programmed death (PD)-1, have shown remarkable progress. Nevertheless, treatment efficacy in hepatocellular carcinoma (HCC) is notably compromised due to the intricate immune microenvironment. Exploring alternative checkpoints beyond PD-L1/PD-1, including those not located on the cell surface, may improve our understanding of their roles in areas like diagnostic potential and immune tolerance in HCC.
To explore the roles of serum exosomal CD155 (exo-CD155) in HCC.
Experimental study.
We separated and analyzed serum exosomes from HCC patients. We quantified the concentrations of serum soluble CD155 (sCD155) and serum exo-CD155, and examined their association with disease progression, hepatitis B surface antigen (HBsAg) presence, and the concentrations of α-fetoprotein fraction L3 (AFP-L3) or alpha-fetoprotein (AFP). Additionally, we assessed the diagnostic effect through the receiver operating characteristic (ROC) curve, and the immune suppressive effect on natural killer (NK) cells of exo-CD155.
This study reveal elevated exo-CD155 levels in all HCC patients, with a significant increase in early-stage patients, exhibiting normal AFP/AFP-L3 or HBsAg-positive status. Exo-CD155 is linked to the progression of HCC and shows significant diagnostic effectiveness for the disease. Furthermore, the incubation of NK-92MI with exosomes derived from HCC patients leads to a substantial reduction in immune function, which can be partially counteracted with an antibody that blocks T cell immune receptor immunoglobulin and ITIM domains, (TIGIT)-blocking antibody.
These results disclose exo-CD155 shows promise for serving as a biomarker for HCC, especially in early-stage patients or those with normal AFP/AFP-L3 levels. Moreover, serum exosomes from HCC patients suppress NK cell immune functions through the TIGIT/CD155 pathway, contributing to immune tolerance in HCC.
针对肿瘤免疫检查点的靶向治疗，如程序性死亡配体（PD-L）1/程序性死亡（PD）-1，已取得显著进展。然而，由于复杂的免疫微环境，肝细胞癌（HCC）的治疗效果明显受到影响。探索PD-L1/PD-1以外的其他检查点，包括那些不在细胞表面的检查点，可能会增进我们对它们在HCC诊断潜力和免疫耐受等方面作用的理解。
探讨血清外泌体CD155（exo-CD155）在HCC中的作用。
实验研究。
我们分离并分析了HCC患者的血清外泌体。我们定量了血清可溶性CD155（sCD155）和血清exo-CD155的浓度，并检查它们与疾病进展、乙肝表面抗原（HBsAg）存在情况以及甲胎蛋白L3（AFP-L3）或甲胎蛋白（AFP）浓度的关联。此外，我们通过受试者工作特征（ROC）曲线评估诊断效果，以及exo-CD155对自然杀伤（NK）细胞的免疫抑制作用。
本研究揭示所有HCC患者的exo-CD155水平升高，早期患者显著增加，这些患者的AFP/AFP-L3正常或HBsAg呈阳性。Exo-CD155与HCC的进展相关，对该疾病显示出显著的诊断效力。此外，将NK-92MI与来自HCC患者的外泌体共同孵育会导致免疫功能大幅降低，而一种阻断T细胞免疫受体免疫球蛋白和ITIM结构域（TIGIT）的抗体可部分抵消这种降低。
这些结果表明exo-CD155有望作为HCC的生物标志物，尤其是在早期患者或AFP/AFP-L3水平正常的患者中。此外，HCC患者的血清外泌体通过TIGIT/CD155途径抑制NK细胞免疫功能，导致HCC中的免疫耐受。
