Exosomal PD-L1: New Insights Into Tumor Immune Escape Mechanisms and Therapeutic Strategies

Kaijian Zhou,Shu Guo,Qiang Sun,Fei Li,Guoxin Liang

doi:10.3389/fcell.2020.569219

Abstract

As a classical immune checkpoint molecule, PD-L1 on the surface of tumor cells plays a pivotal role in tumor immunosuppression, primarily by inhibiting the antitumor activities of T cells by binding to its receptor PD-1. PD-1/PD-L1 inhibitors have demonstrated unprecedented promise in treating various human cancers with impressive efficacy. However, a significant portion of cancer patients remains less responsive. Therefore, a better understanding of PD-L1-mediated immune escape is imperative. PD-L1 can be expressed on the surface of tumor cells, but it is also found to exist in extracellular forms, such as on exosomes. Recent studies have revealed the importance of exosomal PD-L1 (ExoPD-L1). As an alternative to membrane-bound PD-L1, ExoPD-L1 produced by tumor cells also plays an important regulatory role in the antitumor immune response. We review the recent remarkable findings on the biological functions of ExoPD-L1, including the inhibition of lymphocyte activities, migration to PD-L1-negative tumor cells and immune cells, induction of both local and systemic immunosuppression, and promotion of tumor growth. We also discuss the potential implications of ExoPD-L1 as a predictor for disease progression and treatment response, sensitive methods for detection of circulating ExoPD-L1, and the novel therapeutic strategies combining the inhibition of exosome biogenesis with PD-L1 blockade in the clinic.

Highlights

Programmed cell death protein-ligand 1 (PD-L1) is an immune checkpoint molecule that interacts with programmed cell death protein-1 (PD-1) to mediate immunosuppression (Ribas and HuLieskovan, 2016; Alsaab et al, 2017; Sun et al, 2018; Han et al, 2020)
Exosomal PD-L1 derived from tumors is able to suppress antitumor immunity locally and systemically through ligation of PD-1 on T cells, which facilitates immune escape and tumor progression
Recent studies have revealed that both cell-surface PD-L1 and ExoPD-L1 play crucial roles in immunosuppression, tumor progression, and response to cancer immunotherapy (Zou et al, 2016; Chen G. et al, 2018; Theodoraki et al, 2018b; Fan et al, 2019; Kim et al, 2019; Xie F. et al, 2019; Cordonnier et al, 2020; Huang et al, 2020; Tang et al, 2020)

Summary

INTRODUCTION

Programmed cell death protein-ligand 1 (PD-L1) is an immune checkpoint molecule that interacts with programmed cell death protein-1 (PD-1) to mediate immunosuppression (Ribas and HuLieskovan, 2016; Alsaab et al, 2017; Sun et al, 2018; Han et al, 2020). Recent studies have demonstrated that PD-L1 exists on the surface of exosomes generated by their parental tumor cells (Chen G. et al, 2018; Lubin et al, 2018; Ricklefs et al, 2018; Theodoraki et al, 2018b; Yang et al, 2018; Fan et al, 2019; Kim et al, 2019; Poggio et al, 2019; Cordonnier et al, 2020; Huang et al, 2020). Human ExoPDL1 was found in the circulation of nude mice bearing human melanoma xenografts (Chen G. et al, 2018) Thereby, both human and murine tumor cells can secrete ExoPD-L1 both in vitro and in vivo. Interferon-γ, a typical inflammatory cytokine, upregulates ExoPD-L1 production by melanoma, breast cancer, prostate cancer, glioblastoma, and non-small cell lung

Method

CONCLUDING REMARKS