WITHDRAWN: Immune imbalance of PD-1 and 1 PD-Ls in liver tissues from patients with Hepatitis B-related hepatocellular carcinoma

Abstract

// Yong Liu 1,2 , Guiyang Wang 3 , Rui Huang 3 , Yingying Hao 4 , Haiyan Chang 3 , Chen Tian 3 , Yang Li 3 , Xiang-An Zhao 3 , Juan Xia 3 , Yuxin Chen 3,5 and Chao Wu 3 1 Department of Experimental Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China 2 Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing, China 3 Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China 4 Department of Intensive Care Units, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China 5 Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China Correspondence to: Chao Wu, email: dr.wu@nju.edu.cn Yuxin Chen, email: yuxin_chen2015@163.com Keywords : PD-1; PD-L1; PD-L2; microenvironment; hepatitis B-related hepatocellular carcinoma Received: October 27, 2017     Accepted: December 05, 2017     Epub: January 12, 2018 Abstract 2 Dysregulated immune microenvironment, such as imbalance of programmed death-1 (PD-1) and its ligands (PD-Ls), plays a key role in hepatocarcinogenesis. Here we investigate the key immune checkpoint molecules, PD-1/PD-Ls, in liver tissues from patients with hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). We show that the characteristic of T cells in peripheral blood does not fully reflect the changes of immune microenvironment in tumor tissues. There is an imbalanced immune microenvironment in liver tissues, characterized by increased CD4/CD8 ratio and high expression of PD-1 on CD8 T cells in tumor tissues. Soluble PD-1 (sPD-1) levels in tumor tissues are increased, whereas sPD-L1 and sPD-L2 levels are decreased. Compared with control subjects, the patients with HBV-related HCC have higher serum sPD-1 and sPD-L1 levels, lower serum sPD-L2 levels. We also show that the altered immune microenvironment is not only found in tumor tissues, but also in non-tumor tissues from HBV-related HCC patients. The correlation between PD-1 and PD-L1 increases successively in hepatocellular carcinomas tissues, paracancerous tissues and adjacent non-tumor tissues. In tumor tissues, sPD-1 levels are negatively correlated with clinicopathological stages of HCC, while serum sPD-L1 levels have positive correlation with the clinicopathological stages. Combined, HBV infection alone may not affect the characteristics of T cell subpopulations, but might be related with the higher PD-1 levels in liver tissues. The immune imbalance of PD-1/PD-Ls in liver tissues may have important role in tumor microenvironment and immune escape, closely related with tumor initiation and progression.