Journal
SIGNAL TRANSDUCTION AND TARGETED THERAPY
Volume 6, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41392-021-00784-0
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Funding
- National Key Project for Infectious Diseases of China [2017ZX10203207]
- National Natural Science Foundation of China [81672848, 81972703, 82072696]
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The study reveals that GOLM1 induces CD8(+) T cell suppression in HCC by promoting PD-L1 stabilization and transporting PD-L1 into TAMs via exosomes. Targeting PD-L1(+) TAMs could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.
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.
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