虽然免疫检查点抑制剂（ICIs）在治疗转移性黑色素瘤方面很有前景，但大约一半的患者对其反应不佳。肿瘤中低水平的人类白细胞抗原-DR (HLA-DR) 已被证明会对预后和 ICI 反应产生负面影响。溶血磷脂酸（LPA）由黑色素瘤大量产生，并且大量存在于肿瘤微环境中。 LPA诱导肿瘤细胞释放多种细胞因子和趋化因子，影响癌症的发生、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 表达中的作用及其在人黑色素瘤细胞中的潜在机制。我们发现，LPA (0.001-10μM) 通过激活 HEK293T 细胞中的 LPAR1，剂量依赖性地增加 DR6 转录物水平。 NF-κB1 的敲低消除了 LPA 增加的 DR6 表达，而不影响 A2058 和 A375 黑色素瘤细胞系中的基础 DR6 表达。 LPA (10μM) 显着增加 A2058 和 A375 黑色素瘤细胞中 IL-10 的转录，但通过药物抑制 LPAR1 或敲低 DR6 可以消除该作用。我们发现人类黑色素瘤组织中 LPAR1、DR6 和 IL-10 的表达之间存在统计学显着相关性，并且 LPAR1 表达增加与 ICI 治疗有效性降低之间存在关联。我们证明，LPA (10μM) 通过激活 LPAR1-DR6-IL-10 通路，显着抑制 A375 和 A2058 黑色素瘤细胞中的 HLA-DR 表达。这些数据表明，LPAR1-DR6-IL-10 自分泌环路可能构成肿瘤细胞通过降低 HLA-DR 表达来逃避免疫监视的新机制。© 2024。作者。

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.© 2024. The Author(s).