Biological Characteristics and Clinical Significance of Soluble PD-1/PD-L1 and Exosomal PD-L1 in Cancer

Abstract

The immune checkpoint pathway consisting of the cell membrane-bound molecule programmed death protein 1 (PD-1) and its ligand PD-L1 has been found to mediate negative regulatory signals that effectively inhibit T-cell proliferation and function and impair antitumor immune responses. Considerable evidence suggests that the PD-1/PD-L1 pathway is responsible for tumor immune tolerance and immune escape. Blockage of this pathway has been found to reverse T lymphocyte depletion and restore antitumor immunity. Antagonists targeting this pathway have shown significant clinical activity in specific cancer types. Although originally identified as membrane-type molecules, several other forms of PD-1/PD-L1 have been detected in the blood of cancer patients, including soluble PD-1/PD-L1 (sPD-1/sPD-L1) and exosomal PD-L1 (exoPD-L1), increasing the composition and functional complications of the PD-1/PD-L1 signaling pathway. For example, sPD-1 has been shown to block the PD-1/PD-L immunosuppressive pathway by binding to PD-L1 and PD-L2, whereas the role of sPD-L1 and its mechanism of action in cancer remain unclear. In addition, many studies have investigated the roles of exoPD-L1 in immunosuppression, as a biomarker for tumor progression and as a predictive biomarker for response to immunotherapy. This review describes the molecular mechanisms underlying the generation of sPD-1/sPD-L1 and exoPD-L1, along with their biological activities and methods of detection. In addition, this review discusses the clinical importance of sPD-1/sPD-L1 and exoPD-L1 in cancer, including their predictive and prognostic roles and the effects of treatments that target these molecules.

Keywords: biological activity; cancer; efficacy prediction; exosomal PD-L1; immunotherapy; prognosis; soluble PD-1; soluble PD-L1.

Figure 1

Mechanisms responsible for the generation of soluble PD-1 and PD-L1. (A) Generation of soluble PD-1 from splice variants of PD-1 mRNA. Full length PD-1 (flPD-1) mRNA contains five exons (exons 1–5), which encode a short signal sequence, an immunoglobulin (Ig) domain, the stalk and transmembrane (TM) domain, a 12 amino acid (aa) sequence that marks the beginning of the cytoplasmic domain, the C-terminal intracellular (IC) domain and a long 3’UTR, respectively. Four splice variants of PD-1 mRNA, PD-1Deltaex2, PD-1Deltaex3, PD-1Deltaex2/3, and PD-1Deltaex2/3/4, have been cloned from human peripheral blood mononuclear cells (PBMCs). PD-1Deltaex3 only lacks exon 3, but retains an extracellular Ig domain. Translation of this mRNA results in a soluble form PD-1. (B) Generation of soluble PD-L1 by proteolytic cleavage of membrane-bound PD-L1. Several proteases, including MMPs and ADAMs, are capable of cleaving membrane-bound PD-L1, releasing soluble PD-L1.

Figure 2

Biological activity of membrane and soluble PD-1/PD-L1 in tumor immunity. (A) The complete activation of T cells relies on two signals, with the first signal provided by the specific binding of T-cell receptor (TCR) to major histocompatibility complex (MHC) and the second signal provided by the interaction of CD28 on T cell surfaces with co-stimulatory molecules CD80/CD86 expressed by antigen-presenting cells (APCs). (B) The mechanism of PD-1/PD-L1 signaling involves the recruitment of the Src homology 2 domain containing phosphatases 2 (SHP2) to the PD-1 cytoplasmic domain, which dephosphorylates signaling molecules of the PI3K-AKT and MAPK pathways, thereby restricting T-cell proliferation, activation and survival. (C) sPD-1 has been found to suppress the interactions of PD-1 with PD-L1 and PD-L2 and the interaction of PD-L1 with CD80. However, sPD-1 may also have reverse signaling effects on APCs via the PD-L1/PD-L2 pathway and inhibits T cell function. (D) sPD-L1, like mPD-L1, binds to PD-1 to transmit negative regulatory signals.