MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling

The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs.

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Dario Zimmerli #, Chiara S Brambillasca #, Francien Talens #, Jinhyuk Bhin, Renske Linstra, Lou Romanens, Arkajyoti Bhattacharya, Stacey E P Joosten, Ana Moises Da Silva, Nuno Padrao, Max D Wellenstein, Kelly Kersten, Mart de Boo, Maurits Roorda, Linda Henneman, Roebi de Bruijn, Stefano Annunziato, Eline van der Burg, Anne Paulien Drenth, Catrin Lutz, Theresa Endres, Marieke van de Ven, Martin Eilers, Lodewyk Wessels, Karin E de Visser, Wilbert Zwart, Rudolf S N Fehrmann, Marcel A T M van Vugt, Jos Jonkers

期刊 Nat Commun
影响因子 16.6
起止号 2022 Nov 2;13(1):6579.
种属 Mouse
技术平台抗体芯片
应用领域免疫/内分泌
研究方向免疫/内分泌
疾病类型乳腺癌
检测蛋白 Adiponectin/Acrp30,DPPIV/CD26,IL-27,Amphiregulin,EGF,IL-28,Angiopoietin-1,Endoglin/CD105,IL-33,Angiopoietin-2,Endostatin,LDL R,Angiopoietin-like 3,Fetuin A/AHSG,Leptin,BAFF/BLyS/TNFSF13B,FGF acidic,LIF,C1q R1/CD93,FGF-21,Lipocalin-2/NGAL,CCL2/JE/MCP-1,Flt-3 Ligand,LIX,CCL3/CCL4 MIP-1 alpha/beta,Gas6,M-CSF,CCL5/RANTES,G-CSF,MMP-2,CCL6/C10,GDF-15,MMP-3,CCL11/Eotaxin,GM-CSF,MMP-9,CCL12/MCP-5,HGF,Myeloperoxidase,CCL17/TARC,ICAM-1/CD54,Osteopontin (OPN),CCL19/MIP-3 beta,IFN-gamma,Osteoprotegerin/TNFRSF11B,CCL20/MIP-3 alpha,IGFBP-1,PD-ECGF/Thymidine phosphorylase,CCL21/6Ckine,IGFBP-2,PDGF-BB,CCL22/MDC,IGFBP-3,Pentraxin 2/SAP,CD14,IGFBP-5,Pentraxin 3/ TSG-14,CD40/TNFRSF5,IGFBP-6,Periostin/OSF-2,CD160,IL-1 alpha/IL1F1,Pref-1/DLK-1/FA1,Chemerin,IL-1 beta/IL-1F2,Proliferin,Chitinase 3-like 1,IL-1ra/IL-1F3,Proprotein Convertase 9/PCSK9,Coagulation Factor III/Tissue Factor,IL-2,RAGE,Complement Component C5/C5a,IL-3,RBP4,Complement Factor D,IL-4,Reg3G,C-Reactive Protein/CRP,IL-5,Resistin,CX3CL1/Fractalkine,IL-6,E-Selectin/CD62E,CXCL1/KC,IL-7,P-Selectin/CD62P,CXCL2/MIP-2,IL-10,Serpin E1/PAI-1,CXCL9/MIG,IL-11,Serpin F1/PEDF,CXCL10/IP-10,IL-12p40,Thrombopoietin,CXCL11/I-TAC,IL-13,TIM-1/KIM-1/HAVCR,CXCL13/BLC/BCA-1,IL-15,TNF-alpha,CXCL16,IL-17A,VCAM-1/CD106,Cystatin C,IL-22,VEGF,Dkk-1,IL-23,WISP-1/CCN4

Abstract

The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs.

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