ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation

Monypenny, James; Milewicz, Hanna; Flores-Borja, Fabián; Weitsman, Gregory; Cheung, Anthony; Chowdhury, R; Burgoyne, Thomas; Arulappu, Appitha; Lawler, Katherine; Barber, Paul R.; Vicencio, José M.; Keppler, Melanie D.; Wulaningsih, Wahyu; Davidson, Sean M.; Fraternali, Franca; Woodman, Natalie; Turmaine, Mark; Gillett, Cheryl; Franz, Dafne; Quezada, Sergio A.; Futter, Clare E.; Kriegsheim, Alex von; Kölch, Walter; Vojnovic, Borivoj; Carlton, Jeremy G.; Ng, Tony

doi:10.1016/j.celrep.2018.06.066

Cited by 108 publications

(112 citation statements)

References 36 publications

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“…In addition, ALIX controls exosomal cargo incorporation. PD-L1 is mis-secreted in the absence of ALIX (24,30). ALIX can also regulate PD-L1 surface presentation in basal-like breast cancer (BLBC) cells (30,31).…”

Section: Pd-l1 Packaged In Exosome At Subcellular Structurementioning

confidence: 99%

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: Pd-l1 Packaged In Exosome At Subcellular Structurementioning

confidence: 99%

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

et al. 2020

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“…The ESCRT‐associated protein ALIX is reported to be a critical regulator of both EGFR activity and PD‐L1 surface presentation in basal‐like breast cancer cells. ALIX depletion was found to extend stimulation‐induced EGFR activity, resulting in defective MVB‐mediated PD‐L1 trafficking, reduced exosome‐mediated PD‐L1 secretion, and the redistribution of PD‐L1 to the cell surface . Research is now being conducted to test the ability of TDE‐expressed immune checkpoint inhibitors to target and block these immunosuppressive mechanisms to enhance the ability of endogenous immune cells to deliver robust and effective clinical responses.…”

Section: Tde‐mediated Immune Suppressionmentioning

confidence: 99%

“…Detailed characterization of inhibitory immune checkpoint receptors and ligands expressed on cancer cells and cancer‐directed immune cells is necessary to assess the potential efficacy of specific immune checkpoint inhibitors. Better understanding of the immunosuppressive contributions arising from TDEs and exosomes derived from immune cells is critical to develop such strategies …”

Section: Tde‐mediated Immune Suppressionmentioning

confidence: 99%

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Tumor‐derived exosomes (TDEs): How to avoid the sting in the tail

Wan

Ning

Spiegel

et al. 2019

Medicinal Research Reviews

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Exosomes are abundantly secreted extracellular vesicles that accumulate in the circulation and are of great interest for disease diagnosis and evaluation since their contents reflects the phenotype of their cell of origin. Tumor‐derived exosomes (TDEs) are of particular interest for cancer diagnosis and therapy, since most tumor demonstrate highly elevated exosome secretion rates and provide specific information about the genotype of a tumor and its response to treatment. TDEs also contain regulatory factors that can alter the phenotypes of local and distant tissue sites and alter immune cell functions to promote tumor progression. The abundance, information content, regulatory potential, in vivo half‐life, and physical durability of exosomes suggest that TDEs may represent a superior source of diagnostic biomarkers and treatment targets than other materials currently under investigation. This review will summarize current information on mechanisms that may differentially regulate TDE biogenesis, TDE effects on the immune system that promote tumor survival, growth, and metastasis, and new approaches understudy to counteract or utilize TDE properties in cancer therapies.

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“…ALIX depletion resulted in prolonged and enhanced stimulation, which induced epidermal growth factor receptor activity and defective PD‐L1 trafficking through the multivesicular body, reduced exosomal secretion, and its redistribution to the cell surface. Increased surface PD‐L1 expression conferred an epidermal growth factor receptor‐dependent immunosuppressive phenotype on ALIX‐depleted cells to modulate immunosuppression in basal‐like breast cancer …”

Section: Immunotherapymentioning

confidence: 99%

Potential role of exosomes in cancer therapy

Zhao

Xie

2019

Precision Radiation Oncology

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Cancer is a major public health problem, and >18.1 million new cancer cases are diagnosed annually. Cancer can be treated with the help of several methods, such as surgery, chemotherapy, radiotherapy, and immunotherapy. Chemoresistance causes disease relapse and metastasis, and is a main obstacle to cancer therapy. The function of exosomes has been recently highlighted in cancer treatment and therapeutic resistance. Exosomes, described as nanovesicles secreted by multiple mammalian cell types, play important roles in intercellular communication by acting as carriers of functional contents, such as proteins, non‐coding RNA (miRNA, lncRNA), mRNAs, and lipids. In addition, exosomes might participate in cancer therapeutic resistance. The present review aimed to describe the function of exosomes in different types of cancer, with emphasis on their role in chemoresistance, hoping to provide novel insights on their implications in cancer therapy.

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ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation

Cited by 108 publications

References 36 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

Tumor‐derived exosomes (TDEs): How to avoid the sting in the tail

Potential role of exosomes in cancer therapy

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