Exosomal PD-L1 Retains Immunosuppressive Activity and is Associated with Gastric Cancer Prognosis

Fan, Yibo; Che, Xiaofang; Qu, Junle; Hou, Kezuo; Wen, Ti; Li, Zhi; Li, Ce; Wang, Shuo; Xu, Ling; Liu, Yunpeng; Qu, Xiujuan

doi:10.1245/s10434-019-07431-7

Cited by 148 publications

(157 citation statements)

References 27 publications

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“…Exosomal PD-L1 secreted by melanoma, breast cancer, and gastric cancer cells has immunosuppressive effects (8,9,14). Chen et al proposed a model of melanoma in which exosomal PD-L1 can fight circulating T cells remotely, even before T cells approach the melanoma cells, like a biological unmanned aerial vehicle (UAV) (8) (Figure 2A).…”

Section: Cancer Biology Of Exosomal Pd-l1 Exosomal Pd-l1 Induces Immumentioning

confidence: 99%

“…Chen et al have recently shown that PD-L1 is preferentially enriched in exosomes, when compared with that in melanoma microvesicles, suggesting that exosomes are the primary source of PD-L1 among EVs in this cancer type (8). Other studies have confirmed that exosomal PD-L1, EVs containing PD-L1, and exosomal PD-L1 mRNA can be detected in melanoma, prostate cancer, breast cancer, glioblastoma, head and neck cancer, lung cancer, and other tumors (8)(9)(10)(11)(12)(13)(14)(15) (Table 1).…”

Section: Introductionmentioning

confidence: 96%

“…Tumor-derived exosomal PD-L1 combines the advantages of exosomes and PD-L1 to mediate an immunosuppressive effect. Exosomal PD-L1 is more stable and not easily degraded by proteolytic enzymes (14). Additionally, exosomal PD-L1 might exert stronger immunomodulatory effects in circulation and tumor microenvironments.…”

Section: Introductionmentioning

confidence: 99%

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The Biogenesis, Biology, and Clinical Significance of Exosomal PD-L1 in Cancer

et al. 2020

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The exosome serves as a trafficking vehicle for transport of programmed death-ligand 1 (PD-L1) into receptor cells. In tumor microenvironment, distant tumor cells can remotely attack activated T cells by exosomal PD-L1. Here, we summerize the biogenesis and transport process of exosomal PD-L1. Then, we focus on the cancer biology of exosomal PD-L1 in immunosuppression and the mechanism by which it inhibits T cells. Finally, we highlight the prospects of exosomal PD-L1 as a tumor biomarker and its significance in immunotherapy. In addition, we discuss the new challenges faced in researching and utilizing exosomal PD-L1. This review may shed light on the exosomal PD-L1 from the bench to the clinic. Exosomes serve as trafficking vehicles for transport of programmed death-ligand 1 (PD-L1) into receptor cells. In tumor microenvironment, distant tumor cells can remotely attack activated T cells through exosomal PD-L1. Here, we have summarized the biogenesis and transport of exosomal PD-L1. Next, we focused on the cancer biology of exosomal PD-L1 in immunosuppression and the mechanism by which it inhibits T cells. Finally, we highlighted the prospects of exosomal PD-L1 as a tumor biomarker and its significance in immunotherapy. In addition, we have discussed the new challenges faced in studying and utilizing exosomal PD-L1. This review may shed light on the translation of exosomal PD-L1 from bench to clinic.

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Section: Cancer Biology Of Exosomal Pd-l1 Exosomal Pd-l1 Induces Immumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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The Biogenesis, Biology, and Clinical Significance of Exosomal PD-L1 in Cancer

et al. 2020

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“…Soluble PD-L1 (sPD-L1) is frequently detected in the blood of cancer patients. Three mechanisms can contribute to the release of PD-L1 into circulation: alternatively spliced transcripts [ 153 , 154 ], release of PD-L1 associated with extracellular vesicles such as exosomes [ 155 , 156 ] and proteolytical cleavage from the surface of PD-L1-expressing cancer- and non-cancer cells [ 157 ].…”

Section: Regulation Pd-l1 Protein Expressionmentioning

confidence: 99%

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Shklovskaya

Rizos

2020

IJMS

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Immunotherapies blocking immune inhibitory receptors programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) on T-cells have dramatically improved patient outcomes in a range of advanced cancers. However, the lack of response, and the development of resistance remain major obstacles to long-term improvements in patient outcomes. There is significant interest in the clinical use of biomarkers to improve patient selection, and the expression of PD-1 ligand 1 (PD-L1) is often reported as a potential biomarker of response. However, accumulating evidence suggests that the predictive value of PD-L1 expression in tumor biopsies is relatively low due, in part, to its complex biology. In this review, we discuss the biological consequences of PD-L1 expression by various cell types within the tumor microenvironment, and the complex mechanisms that regulate PD-L1 expression at the genomic, transcriptomic and proteomic levels.

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“…By conducting the preliminary experiments, we surprisingly found that low-dose DB regulated CSCs properties in GC cells, however, up until now, no existed literatures reported the link between DB and cell stemness. Programmed death ligand-1 (PD-L1) functioned as an oncogene to facilitate GC progression [20,21], which was also associated with immune evasion in tumor microenvironment [22,23]. Aside from that, Y Zuo et al validated that PD-L1 promoted cisplatinresistance in ovarian cancer [24], and Fang Wei et al found that upregulation of PD-L1 speci cally promoted CSCs expansion in colorectal cancer [25].…”

Section: Introductionmentioning

confidence: 99%

Low-dose Diosbulbin-B (DB) Regulates Tumor-Intrinsic PD-L1/NLRP3 Signaling Pathway to Increase Cisplatin-Sensitivity in Gastric Cancer (GC)

Qiu

Xue

2020

Preprint

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Background: Generation of cisplatin (DDP)-resistance by gastric cancer (GC) cells seriously limits the therapeutic efficacy of this drug in clinic, and recent data suggested that Diosbulbin-B (DB), the main anti-tumor compound of Dioscorea bulbifera L, was effective to improve cisplatin-sensitivity in GC cells. However, the underlying mechanisms are still largely unknown.Methods: Genes expressions were determined by Real-Time qPCR and Western Blot. Cell viability was evaluated by cell counting kit-8 and trypan blue staining assay. Annexin V-FITC/PI double staining assay was used to examine cell apoptosis. The Spheroid formation assay was used to evaluated cell stemness. Immunohistochemistry (IHC) was employed to examine the expressions and localization of Ki67 protein in mice tumor tissues.Results: Here we found that low-dose DB (12.5 μM) downregulated PD-L1 to activate NLRP3-medicated pyroptosis, and inhibited cancer stem cells (CSCs) properties, to sensitize cisplatin-resistant GC (CR-GC) cells to cisplatin. Mechanistically, the CR-GC cells were obtained, and either low-dose DB or cisplatin alone had little effects on cell viability in CR-GC cells, while low-dose DB significantly induced apoptotic cell death in cisplatin treated CR-GC cells. In addition, low-dose DB triggered cell pyroptosis in CR-GC cells stimulated with cisplatin, which were abrogated by silencing NLRP3. Next, CSCs tended to be enriched in CR-GC cells, instead of their parental cisplatin-sensitive GC (CS-GC) cells, and low-dose DB (12.5 μM) inhibited spheroid formation and stemness biomarkers (CD44, CD133, SOX2, OCT4 and Nanog) expressions to eliminate CSCs in CR-GC cells, which were reversed by upregulating programmed death ligand-1 (PD-L1). Furthermore, we proved that PD-L1 negatively regulated NLRP3 in CR-GC cells, and low-dose DB (12.5 μM) activated NLRP3-mediated pyroptotic cell death in cisplatin treated CR-GC cells by downregulating PD-L1. Also, low-dose DB aggravated the inhibiting effects of cisplatin on tumorigenesis of CR-GC cells in vivo. Conclusions: Collectively, low-dose DB (12.5 μM) regulated intrinsic PD-L1/NLRP3 pathway to improve cisplatin-sensitivity in CR-GC cells, and this study provided alternative therapy treatments for GC.

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Exosomal PD-L1 Retains Immunosuppressive Activity and is Associated with Gastric Cancer Prognosis

Cited by 148 publications

References 27 publications

The Biogenesis, Biology, and Clinical Significance of Exosomal PD-L1 in Cancer

The Biogenesis, Biology, and Clinical Significance of Exosomal PD-L1 in Cancer

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Low-dose Diosbulbin-B (DB) Regulates Tumor-Intrinsic PD-L1/NLRP3 Signaling Pathway to Increase Cisplatin-Sensitivity in Gastric Cancer (GC)

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