PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer.

Yali Wang,Hua Xiong,Yilu Zhou,Xiuqiong Chen,Yongbiao Huang,Hong Qiu,Wan Qin,Jinfang Su,Yanmei Zou,Rui Chen,Yihua Wang,Kun Zheng,Xianglin Yuan

doi:10.3389/fimmu.2021.762989

Abstract

Despite recent improvements in treatment modalities, pancreatic cancer remains a highly lethal tumor with mortality rate increasing every year. Poly (ADP-ribose) polymerase (PARP) inhibitors are now used in pancreatic cancer as a breakthrough in targeted therapy. This study focused on whether PARP inhibitors (PARPis) can affect programmed death ligand-1 (PD-L1) expression in pancreatic cancer and whether immune checkpoint inhibitors of PD-L1/programmed death 1 (PD-1) can enhance the anti-tumor effects of PARPis. Here we found that PARPi, pamiparib, up-regulated PD-L1 expression on the surface of pancreatic cancer cells in vitro and in vivo. Mechanistically, pamiparib induced PD-L1 expression via JAK2/STAT3 pathway, at least partially, in pancreatic cancer. Importantly, pamiparib attenuated tumor growth; while co-administration of pamiparib with PD-L1 blockers significantly improved the therapeutic efficacy in vivo compared with monotherapy. Combination therapy resulted in an altered tumor immune microenvironment with a significant increase in windiness of CD8+ T cells, suggesting a potential role of CD8+ T cells in the combination therapy. Together, this study provides evidence for the clinical application of PARPis with anti-PD-L1/PD-1 drugs in the treatment of pancreatic cancer.

Highlights

Pancreatic cancer is an extremely lethal disease with a poor prognosis
Immune checkpoint inhibitors are ineffective in pancreatic cancer, probably because programmed death ligand-1 (PD-L1) expression is consistently low in various cell subsets of the pancreatic cancer [26,27,28]
It was observed that the use of pamiparib significantly induced apoptosis of pancreatic cancer cells compared to the control group (P < 0.05; Figure 1A)

Summary

Introduction

Pancreatic cancer is an extremely lethal disease with a poor prognosis. It ranks fourth and sixth, respectively, in causing cancer-related deaths in the USA and China [1], with a 5-year survival rate of less than 10% [2]. In addition to traditional chemotherapeutic agents such as gemcitabine or 5-fluorouracil, recent studies have shown that maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors is beneficial for patients with germline BRCA mutations and metastatic pancreatic cancer, and maybe a harbinger of progress in providing targeted therapy [4, 5]. PARP inhibitors (PARPis), whose most extensive mechanism of action is the inhibition on DNA damage repairing, have become promising for several cancer types, among which the clinical application of PARPis in ovarian cancer is the most advanced [10]. When PD-1 binds to PD-L1, activated T cells receive inhibitory signals and cease to produce anti-tumor immune responses [21], rendering PD-L1 a potentially promising target for the cancer immunotherapy [24, 25]. Immune checkpoint inhibitors are ineffective in pancreatic cancer, probably because PD-L1 expression is consistently low in various cell subsets of the pancreatic cancer [26,27,28]

Methods

Results

Conclusion