Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
Department of Infectious Diseases, Huashan Hospital, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
Signal Transduct Target Ther. 2021 Nov 19;6(1):397. doi: 10.1038/s41392-021-00784-0.
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.
免疫抑制微环境在肿瘤进展和免疫治疗反应中起着重要作用。高尔基膜蛋白 1（GOLM1）与肝细胞癌（HCC）的进展和转移相关。然而，关于 GOLM1 在调节免疫抑制环境及其对 HCC 免疫治疗疗效的影响知之甚少。在这项研究中，GOLM1 与浸润性肿瘤相关巨噬细胞（TAMs）呈正相关，这些 TAMs 表达高水平的程序性死亡配体 1（PD-L1），并抑制 CD8 T 细胞。功能获得和功能丧失研究均确定了 GOLM1 与免疫抑制之间的密切相关性。在机制上，GOLM1 促进了 HCC 细胞中 COP9 信号osome5 介导的 PD-L1 去泛素化，并通过抑制 Rab27b 的表达增加了 PD-L1 向外泌体的转运。此外，与来自 HCC 细胞的外泌体共培养上调了巨噬细胞上 PD-L1 的表达。唑来膦酸联合抗 PD-L1 治疗减少了 PD-L1 TAMs 的浸润，并缓解了 CD8 T 细胞的抑制，从而抑制了小鼠 HCC 模型中的肿瘤生长。总之，我们的研究揭示了 GOLM1 通过促进 PD-L1 稳定并通过外泌体依赖将 PD-L1 转运至 TAMs 来诱导 CD8 T 细胞抑制的机制。靶向 PD-L1 TAM 可能是增强 HCC 中抗 PD-L1 治疗疗效的一种新策略。
