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

Gang Chen, Alexander C. Huang, Wei Zhang, Gao Zhang, Min Wu, Wei Xu, Zili Yu, Jiegang Yang, Beike Wang, Honghong Sun, Houfu Xia, Qiwen Man, Wenqun Zhong, Leonardo F. Antelo, Bin Wu, Xuepeng Xiong, Xiaoming Liu, Lei Guan, Ting Li, Shujing Liu & 19 others Ruifeng Yang, Youtao Lu, Liyun Dong, Suzanne McGettigan, Rajasekharan Somasundaram, Ravi Radhakrishnan, Gordon Mills, Yiling Lu, Junhyong Kim, Youhai H. Chen, Haidong M Dong, Yifang Zhao, Giorgos C. Karakousis, Tara C. Mitchell, Lynn M. Schuchter, Meenhard Herlyn, E. John Wherry, Xiaowei Xu, Wei Guo

Research output: Contribution to journalLetter

135 Citations (Scopus)

Abstract

Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2–4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.

Original languageEnglish (US)
Pages (from-to)382-386
Number of pages5
JournalNature
Volume560
Issue number7718
DOIs
StatePublished - Aug 16 2018

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Immunosuppression
Ligands
Neoplasms
T-Lymphocytes
Interferons
Melanoma
Exosomes
Immune Evasion
Death Domain Receptors
Immune System
Therapeutics
Antibodies
Growth

ASJC Scopus subject areas

  • General

Cite this

Chen, G., Huang, A. C., Zhang, W., Zhang, G., Wu, M., Xu, W., ... Guo, W. (2018). Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature, 560(7718), 382-386. https://doi.org/10.1038/s41586-018-0392-8

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, Zili; Yang, Jiegang; Wang, Beike; Sun, Honghong; Xia, Houfu; Man, Qiwen; Zhong, Wenqun; Antelo, Leonardo F.; Wu, Bin; Xiong, Xuepeng; Liu, Xiaoming; Guan, Lei; Li, Ting; Liu, Shujing; Yang, Ruifeng; Lu, Youtao; Dong, Liyun; McGettigan, Suzanne; Somasundaram, Rajasekharan; Radhakrishnan, Ravi; Mills, Gordon; Lu, Yiling; Kim, Junhyong; Chen, Youhai H.; Dong, Haidong M; Zhao, Yifang; Karakousis, Giorgos C.; Mitchell, Tara C.; Schuchter, Lynn M.; Herlyn, Meenhard; Wherry, E. John; Xu, Xiaowei; Guo, Wei.

In: Nature, Vol. 560, No. 7718, 16.08.2018, p. 382-386.

Research output: Contribution to journalLetter

Chen, G, Huang, AC, Zhang, W, Zhang, G, Wu, M, Xu, W, Yu, Z, Yang, J, Wang, B, Sun, H, Xia, H, Man, Q, Zhong, W, Antelo, LF, Wu, B, Xiong, X, Liu, X, Guan, L, Li, T, Liu, S, Yang, R, Lu, Y, Dong, L, McGettigan, S, Somasundaram, R, Radhakrishnan, R, Mills, G, Lu, Y, Kim, J, Chen, YH, Dong, HM, Zhao, Y, Karakousis, GC, Mitchell, TC, Schuchter, LM, Herlyn, M, Wherry, EJ, Xu, X & Guo, W 2018, 'Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response', Nature, vol. 560, no. 7718, pp. 382-386. https://doi.org/10.1038/s41586-018-0392-8
Chen, Gang ; Huang, Alexander C. ; Zhang, Wei ; Zhang, Gao ; Wu, Min ; Xu, Wei ; Yu, Zili ; Yang, Jiegang ; Wang, Beike ; Sun, Honghong ; Xia, Houfu ; Man, Qiwen ; Zhong, Wenqun ; Antelo, Leonardo F. ; Wu, Bin ; Xiong, Xuepeng ; Liu, Xiaoming ; Guan, Lei ; Li, Ting ; Liu, Shujing ; Yang, Ruifeng ; Lu, Youtao ; Dong, Liyun ; McGettigan, Suzanne ; Somasundaram, Rajasekharan ; Radhakrishnan, Ravi ; Mills, Gordon ; Lu, Yiling ; Kim, Junhyong ; Chen, Youhai H. ; Dong, Haidong M ; Zhao, Yifang ; Karakousis, Giorgos C. ; Mitchell, Tara C. ; Schuchter, Lynn M. ; Herlyn, Meenhard ; Wherry, E. John ; Xu, Xiaowei ; Guo, Wei. / Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. In: Nature. 2018 ; Vol. 560, No. 7718. pp. 382-386.
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abstract = "Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2–4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.",
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AU - Chen, Gang

AU - Huang, Alexander C.

AU - Zhang, Wei

AU - Zhang, Gao

AU - Wu, Min

AU - Xu, Wei

AU - Yu, Zili

AU - Yang, Jiegang

AU - Wang, Beike

AU - Sun, Honghong

AU - Xia, Houfu

AU - Man, Qiwen

AU - Zhong, Wenqun

AU - Antelo, Leonardo F.

AU - Wu, Bin

AU - Xiong, Xuepeng

AU - Liu, Xiaoming

AU - Guan, Lei

AU - Li, Ting

AU - Liu, Shujing

AU - Yang, Ruifeng

AU - Lu, Youtao

AU - Dong, Liyun

AU - McGettigan, Suzanne

AU - Somasundaram, Rajasekharan

AU - Radhakrishnan, Ravi

AU - Mills, Gordon

AU - Lu, Yiling

AU - Kim, Junhyong

AU - Chen, Youhai H.

AU - Dong, Haidong M

AU - Zhao, Yifang

AU - Karakousis, Giorgos C.

AU - Mitchell, Tara C.

AU - Schuchter, Lynn M.

AU - Herlyn, Meenhard

AU - Wherry, E. John

AU - Xu, Xiaowei

AU - Guo, Wei

PY - 2018/8/16

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