MEK inhibition activates STAT signaling to increase breast cancer immunogenicity via MHC-I expression  

作　　者：Derek A.Franklin Jamaal L.James Margaret L.Axelrod Justin M.Balko 

机构地区：[1]Department of Medicine,Vanderbilt University Medical Center,Nashville,TN 37232,USA. [2]Department of Pathology,Microbiology,and Immunology,Vanderbilt University Medical Center,Nashville,TN 37232,USA. [3]Breast Cancer Research Program,Vanderbilt University Medical Center,Nashville,TN 37232,USA.

出　　处：《Cancer Drug Resistance》2020年第3期603-612,共10页癌症耐药（英文）

基　　金：Susan G.Komen Career Catalyst Grant CCR14299052(Balko JM),NIH/NCI SPORE 2P50CA098131-17(Balko JM),Department of Defense Era of Hope Award BC170037(Balko JM);the Vanderbilt-Ingram Cancer Center Support Grant P30 CA68485.Additional funding was provided by NIH T32GM007347(Axelrod ML)NIH T32CA009582-31(James JL)and F30CA236157(Axelrod ML).

摘　　要：Aim:Immunotherapy and immune checkpoint inhibitors(ICI)have changed cancer care for many patients;however,breast cancers have exhibited minimal response to single agent ICI therapy.There is a significant need to identify novel targets capable of increasing cancer cell immunogenicity and response to ICIs in breast cancer.Mitogen activated protein kinase(MAPK)signaling is essential for many cellular processes but the relationship between MAPK signaling and cancer cell immunogenicity is less well understood.Recent reports suggest that MEK inhibition(MEKi)affects the tumor-immune microenvironment by altering the expression of interferon responsive PD-L1 and MHC-I through unknown mechanisms.Methods:Using western blotting and flow cytometry,we sought to determine whether MEKi affects JAK-STAT signaling upstream of PD-L1 and MHC-I expression in a panel of mouse mammary cancer and triple negative breast cancer cell lines.Results:The cell lines tested exhibited increased STAT activation in response to MEKi treatment.Furthermore,MEKi-induced MHC-I and PD-L1 expression are dependent upon STAT1 in MMTV-Neu cells.Interestingly,MEKiinduced STAT activation and interferon-responsive protein expression are abrogated with ErbB-family inhibitor co-treatment in MMTV-Neu cells,suggesting ErbB receptor signaling dependence,but not in basal-like cell lines.Importantly,analysis of basal-like breast cancer patient samples exhibited an inverse relationship between STAT1 and Ras/MAPK activation signatures.Conclusion:These findings suggest that MAPK signaling and STAT activation are inversely related in both mouse and human mammary tumors.This work also supports further study of MEKi to increase STAT signaling and potentially,immunotherapy responses through increased MHC-I and PD-L1 expression.

关 键 词：Mitogen activated protein kinase signaling IMMUNOGENICITY MHC-I PD-L1 

分 类 号：R73[医药卫生—肿瘤]