LPA抑制人类黑色素瘤细胞中的HLA-DR表达：涉及LPAR1和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
影响因子:8.40000
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
摘要
尽管免疫检查点抑制剂（ICI）有望治疗转移性黑色素瘤，但大约一半的患者对它们的反应不佳。肿瘤中人类白细胞抗原-DR（HLA-DR）的低水平已显示出负面影响预后和对ICIS的反应。黑色素瘤大量产生溶血磷酸酸（LPA），并且在肿瘤微环境中大量存在。 LPA诱导各种细胞因子和趋化因子从肿瘤细胞中释放，这会影响癌症发育，转移和肿瘤免疫。在本研究中，我们研究了LPA诱导的IL-10释放在调节HLA-DR表达和人黑色素瘤细胞中的潜在机制中的作用。我们表明，通过激活HEK293T细胞中的LPAR1，LPA（0.001-10μM）剂量依赖性地依赖性地提高了DR6转录水平。 NF-κB1的敲低废除了LPA增强的DR6表达，而不会影响A2058和A375黑色素瘤细胞系中的基础DR6表达。 LPA（10 µM）在A2058和A375黑色素瘤细胞中显着增加了IL-10转录本，通过药理学抑制LPAR1或DR6的敲低消除了效果。我们发现人类黑色素瘤组织中LPAR1，DR6和IL-10的表达与LPAR1表达增加与ICI治疗降低之间的关联之间存在统计学意义的相关性。我们证明，LPA（10 µM）通过激活LPAR1-DR6-IL-10途径明显抑制了A375和A2058黑色素瘤细胞中HLA-DR的表达。这些数据表明，LPAR1-DR6-IL-10自分泌环可能构成肿瘤细胞用来通过降低HLA-DR表达来逃避免疫监视的新机制。
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.