Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jan 28;20(1):14.
doi: 10.1186/s12964-021-00816-w.

Extracellular vesicle PD-L1 in reshaping tumor immune microenvironment: biological function and potential therapy strategies

Jiaxing Liu #  1 , Xueqiang Peng #  1 , Shuo Yang  1 , Xinyu Li  1 , Mingyao Huang  1 , Shibo Wei  1 , Sheng Zhang  1 , Guangpeng He  1 , Hongyu Zheng  1 , Qing Fan  1 , Liang Yang  2 , Hangyu Li  3
Affiliations
Review

Extracellular vesicle PD-L1 in reshaping tumor immune microenvironment: biological function and potential therapy strategies

Jiaxing Liu et al. Cell Commun Signal. .

Abstract

Programmed cell death 1 ligand 1 (PD-L1) is the ligand for programmed death protein-1 (PD-1), is associated with immunosuppression. Signaling via PD-1/PD-L1 will transmits negative regulatory signals to T cells, inducing T-cell inhibition, reducing CD8+ T-cell proliferation, or promoting T-cell apoptosis, which effectively reduces the immune response and leads to large-scale tumor growth. Accordingly, many antibody preparations targeting PD-1 or PD-L1 have been designed to block the binding of these two proteins and restore T-cell proliferation and cytotoxicity of T cells. However, these drugs are ineffective in clinical practice. Recently, numerous of studies have shown that, in addition to the surface of tumor cells, PD-L1 is also found on the surface of extracellular vesicles secreted by these cells. Extracellular vesicle PD-L1 can also interact with PD-1 on the surface of T cells, leading to immunosuppression, and has been proposed as a potential mechanism underlying PD-1/PD-L1-targeted drug resistance. Therefore, it is important to explore the production, regulation and tumor immunosuppression of PD-L1 on the surface of tumor cells and extracellular vesicles, as well as the potential clinical application of extracellular vesicle PD-L1 as tumor biomarkers and therapeutic targets. Video Abstract.

Keywords: Biomarker; Extracellular vesicles; Immune escape; Immunotherapy; PD-L1.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Regulation of PD-L1 expression on the surface of tumor cells. Many factors affect the expression of PD-L1 on tumor cell surface, including genomic alterations and epigenetic, transcriptional, post-transcriptional, and post-translational regulatory mechanisms
Fig. 2
Fig. 2
Abbreviated drawing of the formation process of EV-PD-L1 and its direct and indirect inhibitory effects against T cells. ① The process of Exo-PD-L1 production. ②Microvesicles produced by budding can also carry PD-L1. ③ PD-L1 present on the surface of exosomes secreted by tumor cells directly binds to PD-1 on T cells, inducing an immune checkpoint response that inhibits the activation of T cells and disrupts their function, thus inhibiting antitumor immunity. ④ Exosomes released by tumor cells can mediate the increase of PD-L1 expression on the surface of macrophages, neutrophils or monocytes, and then combine with PD-1 on the surface of T cells to inhibit T cells. ⑤ IFN-γ secreted by T cells can promote the expression of PD-L1 on the surface of tumor cells and exosomes
Fig. 3
Fig. 3
The mechanism of action of anti-PD-1/PD-L1 drugs and the potential mechanism underlying the exosomal PD-L1-mediated resistance to anti-PD-L1 drugs. ① Anti-PD-1/PD-L1 drugs can interact with PD-1/PD-L1, free T cells from the checkpoint block, and restore immune responses. ② and ③ Exo-PD-L1 is thought to contribute to resistance during immunotherapy through two mechanisms. In one, exo-PD-L1 binds to anti-PD-L1 monoclonal antibody (mAb), leading to PD-L1 exposure on the tumor surface (②); in the other, Although anti-PD-L1 mAb can interact with PD-L1 on the surface of tumor, exo-PD-L1 can directly interact with PD-1 on the surface of T cells to inhibit immunity (③)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10:727–742. - PMC - PubMed
    1. Cha JH, Chan LC, Li CW, Hsu JL, Hung MC. Mechanisms controlling PD-L1 expression in cancer. Mol Cell. 2019;76:359–370. - PMC - PubMed
    1. Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I, Vale RD. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355:1428–1433. - PMC - PubMed
    1. Xu R, Rai A, Chen MS, Suwakulsiri W, Greening DW, Simpson RJ. Extracellular vesicles in cancer—implications for future improvements in cancer care. Nat Rev Clin Oncol. 2018;15:617–638. - PubMed
    1. Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J Clin Investig. 2016;126:1139–1143. - PMC - PubMed