首页|LPA suppresses HLA-DR expression in human melanoma cells:a potential immune escape mechanism involving LPAR1 and DR6-mediated release of IL-10

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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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.

lysophosphatidic acid(LPA)melanomadeath receptor 6(DR6)IL-10LPAR1HLA-DR

Enikö Major、Kuan-Hung Lin、Sue Chin Lee、Krisztina Káldi、Balázs Györffy、Gábor J.Tigyi、Zoltán Benyó

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Institute of Translational Medicine,Semmelweis University,Budapest,Hungary

HUN-REN-SU Cerebrovascular and Neurocognitive Disease Research Group,Budapest,Hungary

Department of Physiology,University of Tennessee Health Science Centre,Memphis,TN,USA

Institute of Plant and Microbial Biology,Academia Sinica,Taipei,Taiwan,China

Department of Physiology,Semmelweis University,Budapest,Hungary

Department of Bioinformatics,Semmelweis University,Budapest,Hungary

Department of Biophysics,Medical School,University of Pecs,Pecs,Hungary

Institute of Molecular Life Sciences,HUN-REN Research Centre for Natural Sciences,Budapest,Hungary

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2025

10.1038/s41401-024-01373-x

中国药理学报(英文版)
中科院上海药物研究所

中国药理学报(英文版)

影响因子：0.926
ISSN：1671-4083
年,卷(期)：2025.46(1)