Small extracellular vesicle PD-L1 in cancer: the knowns and unknowns

Abstract

According to the conventional wisdom, programmed death protein 1 ligand (PD-L1)-mediated immunosuppression was based on the physical contact between tumor cells and T cells in the tumor microenvironment. Recent studies demonstrated that PD-L1 was also highly expressed on the surface of tumor cell-derived small extracellular vesicles (sEVs). PD-L1 on sEVs, which could also directly bind to PD-1 on T cells, has a vital function in immunosuppression and immunotherapy resistance. Due to the heterogeneity and dynamic changes of PD-L1 expression on tumor cells, developing sEV PD-L1 as a predictive biomarker for the clinical responses to immunotherapy could be an attractive option. In this review, we summarized and discussed the latest researches and advancements on sEV PD-L1, including the biogenesis and secretion mechanisms, isolation and detection strategies, as well as the biological functions of sEV PD-L1. In the meantime, we highlighted the application potential of sEV PD-L1 as diagnostic and prognostic markers in tumor, especially for predicting the clinical responses to anti-PD-1/PD-L1 immunotherapies. In particular, with the gradual deepening of the studies, challenges and problems regarding the further understanding and application of sEV PD-L1 have begun to emerge. Based on the current research status, we summarized the potential challenges and possible solutions, and prospected several key directions for future studies of sEV PD-L1. Collectively, by highlighting the important knowns and unknowns of sEV PD-L1, our present review would help to light the way forward for the field of sEV PD-L1 and to avoid unnecessary blindness and detours.

Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1

“…In addition, not all the injected αPD-L1 can permeabilize into tumors to be effectively utilized. Due to the small volume and large specific surface area of EVs, EV PD-L1 can easily enter deep tissues [ 26 ]. Thus, TEVs probably more efficiently decoy tumor-permeabilized αPD-L1.…”

“…In addition to TEVs, PD-L1 + EVs can also be produced by other types of cells. TEVs upregulate PD-L1 expression in tumor-associated macrophages [ 27 ], while plasma membrane PD-L1 of parent cells may be the major source of EV PD-L1 [ 26 ]. Therefore, tumor-associated macrophages with upregulated membrane PD-L1 probably secrete EVs with high levels of PD-L1, which may also contribute to the decoy and consumption of αPD-L1.…”

“…Therefore, the parent cells of PD-L1 + EVs are diverse in vivo. Although TEV PD-L1 seems to be a more accurate predictor for immunotherapy [ 26 ], PD-L1 on other EVs should also have the ability to decoy αPD-L1. In addition to exosome-like EVs, our results showed that MVs from tumor cells also contained membrane-associated PD-L1 and could compete with tumor cells to bind αPD-L1.…”

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

“…Recently, it has been shown that PD-L1 present on tumor cell-derived extracellular vesicles (sEVs) play a key role in immunosuppression and resistance to immunotherapies. Therefore, counteracting these vesicles could also improve conventional treatments [73].…”

A New Potential Therapeutic Target for Cancer in Ubiquitin-Like Proteins—UBL3

“…The exosome is an sEV, defined by sizes of 30–150 nm in diameter. The roles of sEVs have been discussed in the context of progression and metastasis in various cancers [ 8 , 9 , 10 ]. sEVs are capable of transporting molecular cargo from one cell to another through vascular vessels and intercellular spaces.…”