Inhibition of PARP Potentiates Immune Checkpoint Therapy through miR-513/PD-L1 Pathway in Hepatocellular Carcinoma

Guoqiang Sun; Ganggang Miao; Zhitao Li; Wubin Zheng; Chunguang Zhou; Guangshun Sun; Hongyong Cao; Zhouxiao Li; Weiwei Tang

doi:10.1155/2022/6988923

Inhibition of PARP Potentiates Immune Checkpoint Therapy through miR-513/PD-L1 Pathway in Hepatocellular Carcinoma

J Oncol. 2022 Apr 13:2022:6988923. doi: 10.1155/2022/6988923. eCollection 2022.

Authors

Guoqiang Sun¹, Ganggang Miao^{1

2}, Zhitao Li¹, Wubin Zheng¹, Chunguang Zhou³, Guangshun Sun¹, Hongyong Cao¹, Zhouxiao Li⁴, Weiwei Tang⁵

Affiliations

¹ Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
² Department of General Surgery, Danyang People's Hospital, Danyang, Jiangsu, China.
³ International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China.

Abstract

Background: The DNA repair enzyme poly(ADP-ribose) polymerase (PARP) is involved in DNA damage repair and cell death. However, the association between PARP's biological activities and the immune microenvironment in hepatocellular carcinoma (HCC) is unclear. The present study will explore whether combining a PARP inhibitor with anti-PD1 might improve the anti-HCC impact and explain how it works.

Method: The PARP inhibitor olaparib was screened out of 867 drugs through Cell Counting Kit 8 (CCK-8) assay. The expression of PARP was verified through the TCGA and TISIDB databases. The impacts exerted by PARP inhibitor olaparib to HCC cells were assessed via wound healing, Transwell, and proliferation assay. In vivo, experiments were performed in a C57BL/6 mouse model to evaluate the function of PARP inhibitor olaparib combination with anti-PD1 in HCC and mice tumors were further detected by immunohistochemically staining.

Result: Olaparib was selected as the research object on the basis of drug screening. The results of the TCGA and Human Protein Atlas databases revealed that PARP was significantly upregulated in carcinoma cell cluster of HCC tissues compared to normal tissues. Higher expression of PARP showed a poorer prognosis based on Kaplan-Meier Plotter. qRT-PCR experiments confirmed that olaparib could increase PD-L1 expression through inhibiting miR-513 in HCC cells. In vivo, experiment confirmed that the combination of olaparib and anti-PD1 could enhance the immunotherapy effect of HCC.

Conclusion: The present study reveals that inhibition of PARP potentiates immune checkpoint therapy through the miR-513/PD-L1 pathway in HCC and the combination of PARP inhibitor olaparib and anti-PD1 is beneficial to HCC therapy.