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Theranostics 2018; 8(20):5690-5702. doi:10.7150/thno.28742 This issue Cite

Research Paper

Clinical significance of PD-1/PD-Ls gene amplification and overexpression in patients with hepatocellular carcinoma

Li-Jie Ma^1*, Fei-Ling Feng^2*, Liang-Qing Dong^1*, Zhao Zhang¹, Meng Duan¹, Long-Zi Liu¹, Jie-Yi Shi¹, Liu-Xiao Yang¹, Zhi-Chao Wang¹, Shu Zhang¹, Zhen-Bin Ding¹, Ai-Wu Ke¹, Ya Cao³, Xiao-Ming Zhang⁴, Jian Zhou^1,5, Jia Fan^1,5, Xiao-Ying Wang^1✉, Qiang Gao^{1,6 ✉}

1. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
2. Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, Naval Military Medical University, Shanghai 200082, China
3. Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, China
4. Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200032, China
5. Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
6. State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China
* These authors contributed equally to this work.

✉ Corresponding author: Qiang Gao, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. E-mail: gaoqiangedu.cn; Xiao-Ying Wang, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. E-mail: wang.xiaoying1sh.cn. More

Abstract

Background: The remarkable clinical activity of PD-1 antibody in advanced hepatocellular carcinoma (HCC) highlights the importance of PD-1/PD-L1-mediated immune escape as therapeutic target in HCC. However, the frequency and prognostic significance of PD-Ls genetic alterations in HCC remain unknown.

Methods: Fluorescence in situ hybridization were used to determine PD-Ls genetic alterations, and qPCR data coupled with immunofluorescence were used to measure the mRNA and protein levels of PD-Ls. Clinical relevance and prognostic value of 9p24.1 genetic alterations were investigated on tissue microarray containing three independent cohorts of 578 HCC patients. The results were further validated in an independent cohort of 442 HCC patients from The Cancer Genome Atlas (TCGA) database.

Results: In total, 7.1%-15.0% for amplification and 15.8%-31.3% for polysomy of 9p24.1 were revealed in three cohorts of HCC patients, similar to the objective response rate of PD-1 antibody in HCC. Patients with 9p24.1 genetic alterations significantly and independently correlated with unfavorable outcomes than those without. FISH and qPCR data coupled with immunofluorescence revealed that genetic alterations of 9p24.1 robustly contributed to PD-L1 and PD-L2 upregulation. In addition, increased expression of PD-L1 instead of PD-L2 also predicted poor survival by multivariate analyses. Meanwhile, high infiltration of PD-1⁺ immune cells also indicated dismal survival in HCC.

Conclusions: Amplification or higher expression of PD-L1 significantly and independently correlated with unfavorable survival in HCC patients, authenticating the PD-1/PD-L1 axis as rational immunotherapeutic targets for HCC.

Keywords: hepatocellular carcinoma, PD-Ls, genetic alteration, FISH, prognosis

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