Trends in Cancer

Trends in Cancer

Volume 6, Issue 7, July 2020, Pages 550-558
Journal home page for Trends in Cancer

Opinion
Exosomal PD-L1: Roles in Tumor Progression and Immunotherapy

https://doi.org/10.1016/j.trecan.2020.03.002Get rights and content

Highlights

  • Levels of exosome PD-L1 expression positively correlate with tumor staging and disease progression and negatively correlate with survival.

  • Tumor-derived exosome PD-L1 is capable of directly binding and inhibiting T cell effector function.

  • Tumor-derived exosomes induce increased PD-L1 expression in macrophages/monocytes.

  • Combination therapy of anti-PD-1 with exosome depletion decreases tumor burden and increases overall survival indicating an antagonistic role for exosome PD-L1 in immune checkpoint blockade therapy.

The use of immune checkpoint therapies targeting programmed death-1 (PD-1) and its ligand (PD-L1) continue to show limited durable success in clinical cases despite widespread application. While some patients achieve complete responses and disease remission, others are completely resistant to the therapy. Recent evidence in the field suggests that tumor-derived exosomes could be responsible for mediating systemic immunosuppression that antagonizes anti-PD-1 checkpoint therapy. In this Opinion article, we discuss our claim that endogenous tumor exosomal PD-L1 and tumor-derived exosome-induced PD-L1 are two of the most notable mechanisms of exosome-mediated resistance against antitumor immunity and we discuss how this resistance could directly influence immune checkpoint therapy failure.

Section snippets

Exosomes and the Cancer Connection

Exosomes are small nanoparticles, 30–150 nm in diameter, that are released via exocytosis from the surface of both normal and tumor cells. Their cargo often contains a wide assortment of RNA, DNA, proteins, miRNAs, metabolites, and other biologically active molecules [1]. They have been isolated from a variety of bodily fluids including bile, blood, breast milk, urine, cerebrospinal fluid, and saliva [2]. Given their abundance and propensity to be found in circulation, exosomes are being

Exosomal Expression of PD-L1

One of the mechanisms by which tumor cells evade immune surveillance is via upregulation of surface expression of PD-L1, which interacts with PD-1 on effector T cells shutting down their antitumor response. Anti-PD-1/PD-L1 monoclonal antibodies (mAbs) have been developed to interfere with this process; however, the overall response is limited [5]. Accumulating evidence suggests that exosomes are a significant source of extratumoral PD-L1 and may be one mechanism contributing to PD-1 antibody

Immunosuppressive Nature of Exosomal PD-L1

The systemic immunosuppressive effects of exosomal PD-L1 can be classified into two categories based on the individual mechanism of suppression: direct endogenous exosomal PD-L1 and indirect exosome-induced PD-L1.

Effect of Exosomal PD-L1 on Immunotherapy

The use of immune checkpoint therapies as first-line treatment for a variety of cancers has become more prominent in recent years [26., 27., 28.]. However, despite widespread use, the clinical responses remain low [5,29]. Therefore, gaining a better understanding of the mechanisms governing PD-L1-mediated immune evasion is necessary. It has been proposed that exosomal expression of PD-L1 is one mechanism by which primary immune checkpoint therapy fails [9]. Here we review the current literature

Concluding Remarks

Tumor-derived exosomes have been shown to promote tumor growth and metastasis in a variety of cancers. In this Opinion article, we have shown how one specific tumor-promoting characteristic, PD-L1 expression on exosomes, imparts an immunosuppressive phenotype through three main mechanisms: direct endogenous exosomal PD-L1, indirect induced PD-L1, and PD-L1-mediated antagonism of immunocheckpoint blockade therapy (Figure 1). In general, exosomes from metastatic tumor cells display increased

References (33)

  • Y. Yang

    Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth

    Cell Res.

    (2018)
  • M. Poggio

    Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory

    Cell

    (2019)
  • G. Chen

    Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response

    Nature

    (2018)
  • M. Cordonnier

    Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients

    J. Extracell. Vesicles

    (2020)
  • M.N. Theodoraki

    Circulating exosomes measure responses to therapy in head and neck cancer patients treated with cetuximab, ipilimumab, and IMRT

    Oncoimmunology

    (2019)
  • M.N. Theodoraki

    Clinical significance of PD-L1+ exosomes in plasma of head and neck cancer patients

    Clin. Cancer Res.

    (2018)

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