ExoPD-L1: an assistant for tumor progression and potential diagnostic marker

Abstract

The proliferation and function of immune cells are often inhibited by the binding of programmed cell-death ligand 1 (PD-L1) to programmed cell-death 1 (PD-1). So far, many studies have shown that this combination poses significant difficulties for cancer treatment. Fortunately, PD-L1/PD-1 blocking therapy has achieved satisfactory results. Exosomes are tiny extracellular vesicle particles with a diameter of 40~160 nm, formed by cells through endocytosis. The exosomes are a natural shelter for many molecules and an important medium for information transmission. The contents of exosomes are composed of DNA, RNA, proteins and lipids etc. They are crucial to antigen presentation, tumor invasion, cell differentiation and migration. In addition to being present on the surface of tumor cells or in soluble form, PD-L1 is carried into the extracellular environment by tumor derived exosomes (TEX). At this time, the exosomes serve as a medium for communication between tumor cells and other cells or tissues and organs. In this review, we will cover the immunosuppressive role of exosomal PD-L1 (ExoPD-L1), ExoPD-L1 regulatory factors and emerging approaches for quantifying and detecting ExoPD-L1. More importantly, we will discuss how targeted ExoPD-L1 and combination therapy can be used to treat cancer more effectively.

Keywords: ExoPD-L1; ExoPD-L1 quantification; combination therapy; immunosuppression; regulatory factors.

Figure 1

Role ExoPD-L1 in Immunosuppression. (A) As part of the typical immunological process, T-cells recognize the tumor-specific antigen and subsequently destroying the tumor cell. (B) On the other hand, ExoPD-L1 derived from tumor cells, causes T cell dysfunction by binding with the PD-1 receptor found on T-cells, which ultimately results in the progression of tumor cells. Moreover, using immune checkpoint inhibitors on the PD-L1 or PD-1 receptors can be restored immune-mediated tumor control and inhibit tumor growth.

Figure 2

Different methods for detecting and quantifying ExoPD-L1. (A) Fe₃O₄@TiO₂ was used to capture ExoPD-L1 in serum, and then PD-L1⁺ exosomes were labeled by SERS tags with anti-PD-L1 antibody for ExoPD-L1 quantification. (B) EPCAM tracked exosomes from tumor cells, and adapters of EpCAM and PD-L1 recognized PD-L1⁺ exosomes, and droplet digital PCR detection reflected the number of ExoPD-L1. (C) Anti-CD63-functionalized magnetic beads and anti-PD-L1-linked capture probes were used to enrich PD-L1⁺ exosomes. DNA amplification with probes as primers reduced environmental pH and released PD-L1⁺ exosomes recognition by stimulating electrochemical reaction.