Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2019; 25(35): 5266-5282
Published online Sep 21, 2019. doi: 10.3748/wjg.v25.i35.5266
Significance of tumor-infiltrating immunocytes for predicting prognosis of hepatitis B virus-related hepatocellular carcinoma
Qi-Feng Chen, Wang Li, Pei-Hong Wu, Lu-Jun Shen, Zi-Lin Huang
Qi-Feng Chen, Wang Li, Pei-Hong Wu, Lu-Jun Shen, Zi-Lin Huang, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong Province, China
Author contributions: Chen QF, Huang ZL, and Li W contributed to study conceptualization; Chen LJ contributed to the methodology; Wu PH provided software; Chen QF, Wu PH, and Huang ZL performed the validation; Chen QF, Wu PH, Huang ZL, and Shen LJ analyzed the data; Chen QF and Li W prepared the original draft; Chen QF, Wu PH, Huang ZL, and Shen LJ reviewed and edited the manuscript; Chen QF contributed to data visualization; Huang ZL supervised the study.
Supported by the National Natural Science Foundation of China, No. 81801804.
Conflict-of-interest statement: The authors deny any conflict of interest.
Data sharing statement: The data used in this manuscript are accessible through
ARRIVE guidelines statement: The ARRIVE guidelines have been adopted.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Zi-Lin Huang, MD, Professor, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center; 651 Dongfeng Road East, Yuexiu District, Guangzhou 510060, Guangdong Province, China.
Telephone: +86-20-87343272 Fax: +86-20-87343392
Received: April 22, 2019
Peer-review started: April 22, 2019
First decision: June 10, 2019
Revised: July 18, 2019
Accepted: August 7, 2019
Article in press: June 10, 2019
Published online: September 21, 2019

Hepatitis B virus (HBV) has been recognized as a leading cause of hepatocellular carcinoma (HCC). Numerous reports suggest that immune infiltration can predict the prognosis of HCC. Nonetheless, no creditable markers for prognosis of HBV-related HCC have been established by systematically assessing the immune-related markers based on tumor transcriptomes.


To establish an immune-related marker based on the cell compositions of immune infiltrate obtained based on tumor transcriptomes, so as to enhance the prediction accuracy of HBV-related HCC prognosis.


RNA expression patterns as well as the relevant clinical data of HCC patients were obtained from The Cancer Genome Atlas. Twenty-two immunocyte fraction types were estimated by cell type identification by estimating relative subsets of RNA transcripts. Subsequently, the least absolute shrinkage and selection operator (LASSO) Cox regression model was employed to construct an immunoscore based on the immunocyte fraction types. Afterwards, the receiver operating characteristic (ROC) curve, Kaplan-Meier, and multivariate Cox analyses were performed. Additionally, a nomogram for prognosis that integrated the immunoscore as well as the clinical features was established. Meanwhile, the correlation of immunoscore with immune genes was also detected, and gene set enrichment analysis (GSEA) of the immunoscore was conducted.


A total of 22 immunocyte fraction types were predicted and compared among the tumor as well as non-tumor samples. An immunoscore was constructed through adopting the LASSO model, which contained eight immunocyte fraction types. Meanwhile, the areas under the ROC curves for the immunoscore biomarker prognostic model were 0.971, 0.912, and 0.975 for 1-, 3-, and 5-year overall survival (OS), respectively. Difference in OS between the high-immunoscore group and the low-immunoscore group was statistically significant [hazard ratio (HR) = 66.007, 95% confidence interval (CI): 8.361-521.105; P < 0.0001]. Moreover, multivariable analysis showed that the immunoscore was an independent factor for predicting the prognosis (HR = 2.997, 95%CI: 1.737-5.170). A nomogram was established, and the C-index was 0.757 (95%CI: 0.648-0.866). The immunoscore showed a significant negative correlation with the expression of PD-1 (P = 0.024), PD-L1 (P = 0.026), PD-L2 (P = 0.029), and CD27 (P = 0.033). Eight pathways were confirmed by GSEA.


The established immunoscore can potentially serve as a candidate marker to estimate the OS for HBV-related HCC cases.

Keywords: Immune risk score, Hepatitis B virus, Hepatocellular carcinoma, Prognostic signature, Cell type identification by estimating relative subsets of RNA transcripts

Core tip: Hepatitis B virus (HBV) infection is epidemiologically related to hepatocellular carcinoma (HCC) development. Immune cells have been recognized to play crucial roles in the prognosis of various types of cancers, including HCC. The immune signature for HBV-related HCC remains unknown. In this study, we explored the proportions of immunocytes, and constructed a robust immune signature to predict the prognosis. These results might contribute to risk stratification and facilitate individualized clinical approach for HBV-related HCC.