Mechanisms underlying low-clinical responses to PD-1/PD-L1 blocking antibodies in immunotherapy of cancer: a key role of exosomal PD-L1

Abstract

Exosomes, as the main group of extracellular vesicles, are biologically active lipid-bilayer vesicles that are naturally released from different types of normal or tumor cells. These vesicles play an important role in intercellular communication and influence the extracellular environment and the immune system. Emerging evidence demonstrates that cancer-derived exosomes are enriched in immunosuppressive proteins, such as the programmed death-ligand 1 (PD-L1). PD-L1 and its receptor programmed cell death protein 1 (PD-1) are the key immune checkpoint molecules that promote tumor progression via negative regulation of immune responses. PDL-1 is highly expressed on the surface of tumor cells and binds to PD-1 on the surface of activated T cells, leading to suppression of T cells, which consequently enables cancer cells to escape antitumor immunity. Currently, there are several Food and Drug Administration-approved monoclonal antibodies blocking PD-1/PD-L1 interaction, which are clinically used for cancer treatment. However, despite impressive treatment outcomes, some patients show poor response to PD-1/PD-L1 blockade. Of note, tumor-derived exosomes containing PD-L1 can recapitulate the effect of cell-surface PD-L1. There is evidence that reveals a significant association between levels of circulating exosomal PD-L1 and rate of response to anti-PD-1/PD-L1 antibody therapy. The present article reviews the role of exosomal PDL-1 in the therapeutic resistance to anti-PD-1/PD-L1 treatment. Importantly, it is suggested that the removal of exosomal PDL-1 could serve as a therapeutic adjuvant for enhancing the efficacy of anti-PD-1/PD-L1 therapy in patients with cancer.

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

“…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 ].…”

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

“…PD-L1 expression on tumor-derived exosomes in the peripheral blood of patients positively correlated with the spread and stage of disease [60]. Accordingly, it has been suggested that removal of exosomes containing PD-L1 could enhance the effectiveness of anti-PD-1/PD-L1 immunotherapy [61].…”

Peripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors

“…Therefore, exosomes can negatively impact anti-tumor immune responses. Notably, some studies have reported the relationship between circulating exosomes and the response to ICI therapy in patients with advanced cancers [86,87,107].…”