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

Jinhong Chen,Jubo Zhang,Yan Geng,Zhifei Lin,Rui Zhang,Minghao Fan,Lun-Xiu Qin,Huliang Jia,Ming Lu,Wenwei Zhu,Lu Liu,Lu Lu

doi:10.1038/s41392-021-00784-0

Jinhong Chen, Jubo Zhang + Show 10 more

Open Access

https://doi.org/10.1038/s41392-021-00784-0

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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.

Highlights

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality, and is an increasing public concern worldwide[1,2]
Overexpression of Golgi membrane protein 1 (GOLM1) is associated with immunosuppressive significantly decreased the population of macrophages and tumor-associated macrophages (TAMs) but did not alter the population of CD8+ T cells and their microenvironment in HCC and immune-escape of tumor cells proliferation (Ki67) significantly, which was consistent with that in
The percentages of macrophages and monocytes were significantly higher in GOLM1-high subgroup compared to GOLM1-low sion on both tumor cells and TAMs (Fig. 2b)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality, and is an increasing public concern worldwide[1,2]. A small number of HCC patients are eligible for curative treatments, such as surgical resection, liver transplantation, and local ablation, because most patients with HCC have already progressed to advanced stages and metastasis at the time of diagnosis[3,4]. The advent of immune checkpoint blockade (ICB) has revolutionized cancer therapeutics. The therapeutic efficacy of ICB therapy is limited by the tumor immune microenvironment, with only 16–20% objective response rates among advanced HCC patients[9]. Analyzing the immune microenvironment of HCC could provide insights into immune evasion mechanisms, which might be helpful to develop more effective immunotherapeutic strategies for HCC

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