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

Yang, Yi; Li, Chia Wei; Chan, Li-Chuan; Wei, Yongkun; Hsu, Jung Mao; Xia, Weiya; Ho, Jin‐Nyoung; Hou, J.; Hsu, Jennifer L.; Sun, Linlin; Hung, Mien‐Chie

doi:10.1038/s41422-018-0060-4

Cited by 383 publications

(398 citation statements)

References 15 publications

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“…In the context of tumor‐derived exosomes, the levels of exosomal programmed death‐ligand 1 (PD‐L1) have been intensively investigated. Studies have shown that levels of exosomal PD‐L1 are associated with tumor progression in different types of malignancies such as metastatic melanoma, glioblastoma, and head and neck and breast cancers . Among various potential mechanisms, Poggio et al .…”

Section: Introductionmentioning

confidence: 99%

“…Studies have shown that levels of exosomal PD-L1 are associated with tumor progression in different types of malignancies such as metastatic melanoma, 19 glioblastoma, 20 and head and neck and breast cancers. 21,22 Among various potential mechanisms, Poggio et al 23 recently noted that exosomal PD-L1 could suppress draining lymph node T-cell activity and enable cancer cells to escape antitumor immunity. However, the significance of intercellular communication by TnTs, first reported in 2004, remains less known.…”

Section: Introductionmentioning

confidence: 99%

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Intercellular transfer of HLA‐G: its potential in cancer immunology

Lin

Yan

2019

Clin & Trans Imm

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Intercellular protein transfer between cancer cells and immune cells is a very common phenomenon that can affect different stages of host antitumor immune responses. HLA‐G, a non‐classical HLA class I antigen, has been observed to be widely expressed in various malignancies, and its immune‐suppressive functions have been well recognised. HLA‐G expression in cancer cells can directly mediate immune tolerance by interacting with inhibitory receptors such as ILT2 and ILT4 expressed on immune cells. Moreover, a network of multiple directional intercellular transfers of HLA‐G among cancer cells and immune cells through trogocytosis, exosomes and tunnelling nanotubes provides malignant cells with an alternative ploy for antigen sharing and induces more complex heterogeneity, to modulate immune responses, ultimately leading to immune evasion, therapy resistance, disease progression and poor clinical outcome. Herein, we discuss the relative aspects of the intercellular transfer of HLA‐G between tumor cells and immune cells and its potential use in tumor immunology research and translational cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intercellular transfer of HLA‐G: its potential in cancer immunology

Lin

Yan

2019

Clin & Trans Imm

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“…As it is well known, tumor cells overexpress co-inhibitory receptor PD-L1 that binds the inhibitory molecule PD-1 on the activated T cells, driving to their inhibition [60,61]. Interestingly, accumulating evidence report that PD-L1 is contained and delivered by sEVs released many tumor types [62][63][64][65][66][67]; moreover, other studies revealed that TEVs can increase PD-L1 expression on monocytes [68,69]. The correlation between TEVs and PD-1/PD-L1 axis will be extensively discussed in paragraph 3.…”

Section: Tevs and T Lymphocyte Cellsmentioning

confidence: 99%

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

Raimondo

Pucci

Alessandro

et al. 2020

IJMS

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The modulation of the immune system is one of the hallmarks of cancer. It is now widely described that cancer cells are able to evade the immune response and thus establish immune tolerance. The exploration of the mechanisms underlying this ability of cancer cells has always attracted the scientific community and is the basis for the development of new promising cancer therapies. Recent evidence has highlighted how extracellular vesicles (EVs) represent a mechanism by which cancer cells promote immune escape by inducing phenotypic changes on different immune cell populations. In this review, we will discuss the recent findings on the role of tumor-derived extracellular vesicles (TEVs) in regulating immune checkpoints, focusing on the PD-L1/PD-1 axis.

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“…As a cell membrane protein, PD‐L1 seems to be packed into and secreted with exosomes from cultured human breast cancer MDA‐MB‐231 cells and mouse mammary tumour 4T1 cells expressing PD‐L1 . Exosomes are components of extracellular microenvironment that are typically spherical and membrane encapsulated marked by CD63 and CD81 proteins in a size of 30–100 nm derived from multi‐vesicular bodies.…”

Section: Pd‐l1 Phosphorylation Palmitoylation Intracellular and Extmentioning

confidence: 99%

“…Exosomes are components of extracellular microenvironment that are typically spherical and membrane encapsulated marked by CD63 and CD81 proteins in a size of 30–100 nm derived from multi‐vesicular bodies. It appears that PD‐L1 in the exosomes is delivered to other cells, including MCF‐7 cells, macrophages and dendritic cells, to induce PD‐L1 on the MCF‐7 cell surface to bind PD‐1, thereby inhibiting CD3/CD28‐induced T‐cell activation with ERK phosphorylation and NF‐κB activation . Analysis of a set of human breast cancer tissue microarrays shows a significant level of co‐localization of PD‐L1 with exosome marker CD63 in association with high stage of cancer progression, and targeting exosome secretion with Tet‐on inducible Rab27a knockdown or exosome secretion inhibitor GW4869 in combination with PD‐L1 antibody in a mouse model produces a significant immunotherapy efficacy, with the tumour suppressive effect being more profound by knocking down Rab27a or inhibitor GW4869 treatment than anti‐PD‐L1 antibody treatment, suggesting controlling PD‐L1 exosome trafficking is critical in preventing negative checkpoint establishment in tumours …”

Section: Pd‐l1 Phosphorylation Palmitoylation Intracellular and Extmentioning

confidence: 99%

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

Wang

et al. 2019

Clin Exp Pharma Physio

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Summary Recent clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein‐1/PD‐1 ligand 1 (PD‐1/PD‐L1) has initiated a new era in the treatment of metastatic cancer. However, greater challenges remain to treat all cancers. The molecular architecture in the immune synapse constituting positive engagements for immune activation and negative checkpoints against immune hyperactivity is regulated dynamically by interaction between proteostasis and tumour microenvironment. This article reviews recent progresses in our understandings of the cellular and molecular mechanisms of the negative checkpoint PD‐1/PD‐L1 behaviours in immune tolerance of tumourigenesis and metastasis. We provide an overview on PD‐L1 gene expression regulation, protein turnover, intra‐ and extracellular trafficking, exosome‐mediated inter‐cellular transport, molecular interface peptide mimetics, inhibitory chemical compounds such as metformin, and antibody dynamics. We summarise PD‐L1 post‐translational modifications including glycosylation, palmitoylation, phosphorylation and ubiquitination, reflecting future research directions and opportunities in identifying tumour‐specific signalling targets, their regulatory molecules and pathways for intervention into various types of cancers.

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

Cited by 383 publications

References 15 publications

Intercellular transfer of HLA‐G: its potential in cancer immunology

Intercellular transfer of HLA‐G: its potential in cancer immunology

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

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