MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling
Zimmerli, Dario; Brambillasca, Chiara S.; Talens, Francien; Bhin, Jinhyuk; Linstra, Renske; Romanens, Lou; Bhattacharya, Arkajyoti; Joosten, Stacey E.P.; Da Silva, Ana Moises; Padrao, Nuno; Wellenstein, Max D.; Kersten, Kelly; de Boo, Mart; Roorda, Maurits; Henneman, Linda; de Bruijn, Roebi; Annunziato, Stefano; van der Burg, Eline; Drenth, Anne Paulien; Lutz, Catrin; Endres, Theresa; van de Ven, Marieke; Eilers, Martin; Wessels, Lodewyk; de Visser, Karin E.; Zwart, Wilbert; Fehrmann, Rudolf S.N.; van Vugt, Marcel A.T.M.; Jonkers, Jos
(2022) Nature Communications, volume 13, issue 1
(Article)
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
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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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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We are grateful for excellent support from the NKI animal facility, RHPC computing facility, flow cytometry facility, animal pathology facility, transgenic facility, preclinical intervention unit, core facility molecular pathology and biobanking (CFMPB), and genomics core facility. We want to thank Martine van Miltenburg for providing data regarding the KP tumor model and Ivo Huijbers for help with generating the mouse models. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative (e-infra160136). Financial support was provided by the Oncode Institute, the Netherlands Organization for Scientific Research (NWO: Cancer Genomics Netherlands (CGCNL), VICI 91814643 (J.J.), VICI 91819616 (K.E.d.V.), VIDI 91713334 (M.A.T.M.v.V.)), the European Research Council (ERC Synergy project CombatCancer (J.J.), ERC-Consolidator grant “TENSION” to (M.A.T.M.v.V.), ERC- Consolidator award InflaMet 615300 (K.E.d.V.)), a National Roadmap grant for Large-Scale Research Facilities from NWO (J.J.), the Dutch Cancer Society KWF13191 and KWF10623 (K.E.d.V.), an unrestricted grant of the Hanarth Fonds (R.S.N.F) and a postdoc mobility grant from the Swiss National Science foundation (D.Z). Funding Information: We are grateful for excellent support from the NKI animal facility, RHPC computing facility, flow cytometry facility, animal pathology facility, transgenic facility, preclinical intervention unit, core facility molecular pathology and biobanking (CFMPB), and genomics core facility. We want to thank Martine van Miltenburg for providing data regarding the KP tumor model and Ivo Huijbers for help with generating the mouse models. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative (e-infra160136). Financial support was provided by the Oncode Institute, the Netherlands Organization for Scientific Research (NWO: Cancer Genomics Netherlands (CGCNL), VICI 91814643 (J.J.), VICI 91819616 (K.E.d.V.), VIDI 91713334 (M.A.T.M.v.V.)), the European Research Council (ERC Synergy project CombatCancer (J.J.), ERC-Consolidator grant “TENSION” to (M.A.T.M.v.V.), ERC- Consolidator award InflaMet 615300 (K.E.d.V.)), a National Roadmap grant for Large-Scale Research Facilities from NWO (J.J.), the Dutch Cancer Society KWF13191 and KWF10623 (K.E.d.V.), an unrestricted grant of the Hanarth Fonds (R.S.N.F) and a postdoc mobility grant from the Swiss National Science foundation (D.Z). Publisher Copyright: © 2022, The Author(s).
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