LPA抑制人类黑色素瘤细胞中的HLA-DR表达：涉及LPAR1与DR6介导的IL-10释放的潜在免疫逃逸机制
LPA suppresses HLA-DR expression in human melanoma cells: a potential immune escape mechanism involving LPAR1 and DR6-mediated release of IL-10
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影响因子:8.4
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2025 Jan
作者:
Enikő Major, Kuan-Hung Lin, Sue Chin Lee, Krisztina Káldi, Balázs Győrffy, Gábor J Tigyi, Zoltán Benyó
DOI:
10.1038/s41401-024-01373-x
摘要
尽管免疫检查点抑制剂（ICIs）在转移性黑色素瘤的治疗中具有潜力，但约一半的患者对其反应不佳。研究显示肿瘤中人类白细胞抗原-DR（HLA-DR）水平低会对预后和ICIs的反应产生负面影响。溶血磷脂酸（LPA）由黑色素瘤大量产生，并在肿瘤微环境中丰富存在。LPA诱导肿瘤细胞分泌多种细胞因子和趋化因子，影响癌症的发展、转移和肿瘤免疫。在本研究中，我们探讨了LPA诱导的IL-10释放在调控人类黑色素瘤细胞中HLA-DR表达中的作用及其潜在机制。结果显示，LPA（0.001-10 μM）通过激活HEK293T细胞中的LPAR1，剂量依赖性地增加DR6转录水平。敲低NF-κB1阻断了LPA引起的DR6表达上调，但不影响A2058和A375黑色素瘤细胞中的基础DR6表达。LPA（10 μM）显著增加A2058和A375黑色素瘤细胞中的IL-10转录本，且该效应被LPAR1的药理抑制或DR6的敲低所逆转。我们发现人类黑色素瘤组织中LPAR1、DR6和IL-10的表达存在统计学上的显著相关性，且LPAR1表达升高与免疫检查点抑制剂治疗效果减弱相关。我们证实，LPA（10 μM）通过激活LPAR1-DR6-IL-10通路，明显抑制A375和A2058黑色素瘤细胞中的HLA-DR表达。这些数据提示，LPAR1-DR6-IL-10自分泌回路可能构成肿瘤细胞逃避免疫监视的新机制，途径是通过减少HLA-DR表达实现的。
Abstract
While immune checkpoint inhibitors (ICIs) are promising in the treatment of metastatic melanoma, about half of patients do not respond well to them. Low levels of human leukocyte antigen-DR (HLA-DR) in tumors have been shown to negatively influence prognosis and response to ICIs. Lysophosphatidic acid (LPA) is produced in large amounts by melanoma and is abundantly present in the tumor microenvironment. LPA induces the release of various cytokines and chemokines from tumor cells, which affect cancer development, metastasis, and tumor immunity. In the present study, we investigated the role of LPA-induced IL-10 release in regulating HLA-DR expression and the underlying mechanisms in human melanoma cells. We showed that LPA (0.001-10 μM) dose-dependently increased DR6 transcript levels through activating LPAR1 in HEK293T cells. Knockdown of NF-κB1 abrogated the LPA-increased DR6 expression without affecting basal DR6 expression in both A2058 and A375 melanoma cell lines. LPA (10 µM) significantly increased IL-10 transcripts in A2058 and A375 melanoma cells, the effect was abolished by pharmacological inhibition of LPAR1 or knockdown of DR6. We found a statistically significant correlation between the expression of LPAR1, DR6 and IL-10 in human melanoma tissue and an association between increased expression of LPAR1 and reduced effectiveness of ICI therapy. We demonstrated that LPA (10 µM) markedly suppressed HLA-DR expression in both A375 and A2058 melanoma cells via activating the LPAR1-DR6-IL-10 pathway. These data suggest that the LPAR1-DR6-IL-10 autocrine loop could constitute a novel mechanism used by tumor cells to evade immunosurveillance by decreasing HLA-DR expression.