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

作　　者：Eniko Major Kuan-Hung Lin Sue Chin Lee Krisztina Kaldi Balazs Gyorffy Gabor J.Tigyi Zoltan Benyo 

机构地区：[1]Institute of Translational Medicine,Semmelweis University,Budapest,Hungary [2]HUN-REN-SU Cerebrovascular and Neurocognitive Disease Research Group,Budapest,Hungary [3]Department of Physiology,University of Tennessee Health Science Centre,Memphis,TN,USA [4]Insttute of Plant and Microbial Biology,Academia Sinica,Taipei,Taiwan,China [5]Department of Physiology,Semmelweis University,Budapest,Hungary [6]Department of Bioinformatics,Semmelweis University,Budapest,Hungary [7]Department of Biophysics,Medical School,University of Pecs,Pecs,Hungary [8]Institute of Molecular Life Sciences,HUN-REN Research Centre for Natural Sciences,Budapest,Hungary

出　　处：《Acta Pharmacologica Sinica》2025年第1期222-230,共9页中国药理学报(英文版)

基　　金：This study was supported by NKFIH K-125174;K-132393;K-135683;K-139230;as well as by 2020-1.1.6-JOvO-2021-00010;TKP2021-EGA-25;EFOP-3.6.3-VEKOP-16-2017-00009 grants;by the Talentum Foundation by Gedeon Richter Plc,NCl grant CA092660;the Harriet Van Vleet Endowment;HUN-REN Hungarian Research Network;The authors thank Dr.Kyle Johnson-Moore from the UTHSC Office of Scientific Writing.Figure 6 and Supplementary Fig.S1 were created with BioRender.com;Open access funding provided by Semmelweis University.

摘　　要：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 ICls.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(0.001-10μM)dosedependently increased DR6 transcript levels through activating LPAR1 in HEK293T cells.Knockdown of NF-kB1 abrogated the LPAincreased DR6 expression without affecting basal DR6 expression in both A2058 and A375 melanoma cell lines.LPA(10μM)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 ICl therapy.We demonstrated that LPA(10μM)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.

关 键 词：lysophosphatidic acid(LPA) MELANOMA death receptor 6(DR6) IL-10 LPAR1 HLA-DR 

分 类 号：R73[医药卫生—肿瘤]