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

Chen, Gang; Huang, Alexander C.; Zhang, Wei; Zhang, Gao; Wu, Min; Xu, Wei; Yu, Zi‐Li; Yang, Jiegang; Wang, Beike; Sun, Honghong; Xia, Hou-Fu; Man, Qi‐Wen; Zhong, Wenqun; Antelo, Leonardo F.; Wu, Bin; Xiong, Xiaolin; Liu, Xiaoming; Guan, Lei; Li, Ting; Liu, Shujing; Yang, Ruifeng; Yi-chen, LU; Dong, Liyun; McGettigan, Suzanne; Somasundaram, Rajasekharan; Radhakrishnan, Ravi; Mills, Gordon B.; Lu, Yiling; Kim, Junhyong; Chen, Youhai H.; Dong, Haidong; Zhao, Yi‐Fang; Karakousis, Giorgos C.; Mitchell, Tara C.; Schuchter, Lynn M.; Herlyn, Meenhard; Wherry, E. John; Xu, Xiaowei; Guo, Wei

doi:10.1038/s41586-018-0392-8

Cited by 1,868 publications

(1,827 citation statements)

References 33 publications

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“…Exosomes are a well‐known driver of cancer progression, and can influence cancer and non‐cancer cell types. Notably, exosomes have recently been implicated in immunosuppression via the presence of PD‐L1 on the surface of melanoma exosomes …”

Section: Introductionmentioning

confidence: 99%

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes

Guo

Lui

Lai

et al. 2019

Intl Journal of Cancer

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Despite recent advances in targeted and immune‐based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A‐replete exosomes, but not RAB27A‐knockdown exosomes, indicating that RAB27A is responsible for the generation of pro‐invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro‐invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma.

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Section: Introductionmentioning

confidence: 99%

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes

Guo

Lui

Lai

et al. 2019

Intl Journal of Cancer

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“…However, not all patients have derived clinical benefits from PD-1/PD-L1 therapy, and the molecular mechanisms underlying the regulation of T cells in GIST are not elucidated. This observation is explained by the latest study, which reports that cancer cells can send out "drones," extracellular vesicles mostly in the form of exosomes that carry PD-L1 on their surface, to battle the immune system from afar 48. Thus, it is critical to determine the mechanism by which PD-1/PD-L1 regulates CD8+ T cells to improve the design of novel CD8+ T-cell-based immunotherapies.In this study, we found that the PD-1/PD-L1 axis contributed to immune evasion and predicted prognosis in GIST.…”

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confidence: 99%

PD‐1/PD‐L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway

et al. 2019

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Objectives:Although targeted therapy has revolutionized the treatment of gastrointestinal stromal tumours (GIST), it is almost never curative in GIST, and resistance commonly develops. One potential strategy is to combine targeted therapy with immunotherapy. Materials and methods:We first studied Programmed cell death 1 ligand 1 (PD-L1) expression and tumour-infiltrating T cells (TILs) in GIST. IFN-γ was used to induce the upregulation of PD-L1 expression in GIST-882 cells, a well-known GIST cell line.CD8+ T-cell apoptosis was determined by flow cytometry. The PI3K/Akt/mTOR levels in CD8+ T cells were examined by Western blotting.Results: PD-L1 expression was an independent factor of poor prognosis in GIST and resulted in exhausted T cells in the TILs population or the blood. Then, we found that PD-L1 blockade alone could not increase tumour cell apoptosis in GIST. The apoptosis rate of CD8+ T cells was higher when T cells were cultured with PD-L1+ GIST-882 cells (GIST-882 cells with high PD-L1 expression) than when T cells were cultured with control GIST-882 cells. However, when the PD-L1 blockade was used, the apoptosis rates of the CD8+ T cells in the two groups became similar. Then, Western blotting showed the PI3K/Akt/mTOR levels of the CD8+ T cells rescued by the PD-1/ PD-L1 blockade were higher than those of the CD8+ T cells not treated with the PD-1/PD-L1 blockade.Conclusions: PD-L1 expression was an independent poor prognosis factor in GIST.PD-1/PD-L1 blockade rescued exhausted CD8+ T cells in GIST via the PI3K/Akt/ mTOR signalling pathway. In GIST, PD-1/PD-L1 not only function as predictive biomarkers but also improve current therapies as treatment targets.

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“…Exosomes from premetastatic melanoma cells were suggested to inhibit metastasis, by instigating immune‐surveillance programs at the metastatic site . Conversely, melanoma‐secreted exosomes were recently shown to contain PD‐L1, that contributed to systemic immunosuppression in patients and with response to immunotherapy . Thus, signaling by tumor‐derived exosomes may be context dependent, and caution should be taken when designing exosome‐targeted therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

Lahav

Adler

Zait

et al. 2019

Intl Journal of Cancer

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The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable “premetastatic niche.” Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma‐derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound‐healing functions, suggesting that tumor cell‐secreted EVs activate distinct CAF characteristics and tumor‐promoting functions. Moreover, melanoma‐secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV‐mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma‐derived EVs reprogram tumor‐promoting functions in stromal cells in a distinct manner, implicating a central role for tumor‐derived EV signaling in promoting the formation of an inflammatory metastatic niche.

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

Cited by 1,868 publications

References 33 publications

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes

PD‐1/PD‐L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway

Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

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