GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages

Abstract The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses. Golgi membrane protein 1 (GOLM1) is correlated to hepatocellular carcinoma (HCC) progression and metastasis. However, little is known about the role of GOLM1 in regulating the im...

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Autores principales:	Jinhong Chen, Zhifei Lin, Lu Liu, Rui Zhang, Yan Geng, Minghao Fan, Wenwei Zhu, Ming Lu, Lu Lu, Huliang Jia, Jubo Zhang, Lun-Xiu Qin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Medicine R Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/655aaff5eb9f4607b3edcf26a5358ed8
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spelling	oai:doaj.org-article:655aaff5eb9f4607b3edcf26a5358ed82021-11-21T12:07:00ZGOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages10.1038/s41392-021-00784-02059-3635https://doaj.org/article/655aaff5eb9f4607b3edcf26a5358ed82021-11-01T00:00:00Zhttps://doi.org/10.1038/s41392-021-00784-0https://doaj.org/toc/2059-3635Abstract The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses. Golgi membrane protein 1 (GOLM1) is correlated to hepatocellular carcinoma (HCC) progression and metastasis. However, little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC. In this study, GOLM1 was positively correlated with infiltrating tumor-associated macrophages (TAMs) expressed high levels of programmed death-ligand 1 (PD-L1) and CD8+ T cell suppression in HCC tissues. Both gain- and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression. In the mechanism, GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression. Furthermore, co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages. Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1+ TAMs infiltration and alleviated CD8+ T cell suppression, resulting in tumor growth inhibition in the mouse HCC model. Together, our study unveils a mechanism by which GOLM1 induces CD8+ T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent. Targeting PD-L1+ TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.Jinhong ChenZhifei LinLu LiuRui ZhangYan GengMinghao FanWenwei ZhuMing LuLu LuHuliang JiaJubo ZhangLun-Xiu QinNature Publishing GrouparticleMedicineRBiology (General)QH301-705.5ENSignal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Biology (General) QH301-705.5
spellingShingle	Medicine R Biology (General) QH301-705.5 Jinhong Chen Zhifei Lin Lu Liu Rui Zhang Yan Geng Minghao Fan Wenwei Zhu Ming Lu Lu Lu Huliang Jia Jubo Zhang Lun-Xiu Qin GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages
description	Abstract The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses. Golgi membrane protein 1 (GOLM1) is correlated to hepatocellular carcinoma (HCC) progression and metastasis. However, little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC. In this study, GOLM1 was positively correlated with infiltrating tumor-associated macrophages (TAMs) expressed high levels of programmed death-ligand 1 (PD-L1) and CD8+ T cell suppression in HCC tissues. Both gain- and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression. In the mechanism, GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression. Furthermore, co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages. Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1+ TAMs infiltration and alleviated CD8+ T cell suppression, resulting in tumor growth inhibition in the mouse HCC model. Together, our study unveils a mechanism by which GOLM1 induces CD8+ T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent. Targeting PD-L1+ TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.
format	article
author	Jinhong Chen Zhifei Lin Lu Liu Rui Zhang Yan Geng Minghao Fan Wenwei Zhu Ming Lu Lu Lu Huliang Jia Jubo Zhang Lun-Xiu Qin
author_facet	Jinhong Chen Zhifei Lin Lu Liu Rui Zhang Yan Geng Minghao Fan Wenwei Zhu Ming Lu Lu Lu Huliang Jia Jubo Zhang Lun-Xiu Qin
author_sort	Jinhong Chen
title	GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages
title_short	GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages
title_full	GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages
title_fullStr	GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages
title_full_unstemmed	GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages
title_sort	golm1 exacerbates cd8+ t cell suppression in hepatocellular carcinoma by promoting exosomal pd-l1 transport into tumor-associated macrophages
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/655aaff5eb9f4607b3edcf26a5358ed8
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GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages

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