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

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.

PD‐L1 and PD‐L2 expression status in relation to chemotherapy in primary and metastatic esophageal squamous cell carcinoma

“…Since it is difficult to evaluate PD‐L1/L2 expression in tissue samples, identifying a new method for evaluating PD‐L1/L2 expression, such as in liquid biopsy, is critical. 34 , 35 , 36 PD‐L1 expression in circulating tumor cells and exosomes in liquid biopsy are reported to be associated with prognosis and the therapeutic effect of ICIs. Further investigation of whether these methods can precisely evaluate PD‐L1/L2 expression in tissue samples is required.…”

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

“…Exosomal PD-L1 directly contributes to immunosuppression, not only in cancer [ 17 ] but also in wound healing [ 18 ]. There are several recent, comprehensive reviews about the biology and specific roles of exoPD-L1 [ 19 , 20 , 21 , 22 , 23 , 24 ]. Exosomal PD-L1 is a target similar to cell membrane PD-L1 (mPD-L1) and different approaches have been designed to reduce exosome biogenesis, secretion or to neutralize secreted exosomes, as recently discussed by Yin and coworkers [ 25 ].…”

Immune Checkpoint Inhibitors Regulate K+ Channel Activity in Cytotoxic T Lymphocytes of Head and Neck Cancer Patients

“…However, while we did not observe any reduction in Kv1.3 activity in HNSCC circulating T cells, there was a profound suppression of this channel activity/expression in TILs, particularly those in close proximity with cancer cells, (Chimote et al, 2018;Newton et al, 2020) where the levels of PD-L1 are higher than in circulation. Secreted PD-L1 is detected in the plasma of HNSCC patients contributing to reduced T cell function (Zhou et al, 2020). While we showed that CD8 + PBTs express PD-L1, we do not know the PD-L1 levels in our cell cultures and how they compare with those of PD-L1-Fc used in our experiments.…”