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

Dario Zimmerli, Chiara S. Brambillasca, Francien Talens, Jinhyuk Bhin, Renske Linstra, Lou Romanens, Arkajyoti Bhattacharya, Stacey E. P. Joosten, Ana Moises Silva, Nuno Padrao, Max D. Wellenstein, Kelly Kersten, Mart Boo, Maurits Roorda, Linda Henneman, Roebi Bruijn, Stefano Annunziato, Eline Burg, Anne Paulien Drenth, Catrin Lutz, Theresa Endres, Marieke Ven, Martin Eilers, Lodewyk Wessels, Karin E. Visser, Wilbert Zwart, Rudolf S. N. Fehrmann (), Marcel A. T. M. Vugt () and Jos Jonkers ()
Additional contact information
Dario Zimmerli: The Netherlands Cancer Institute
Chiara S. Brambillasca: The Netherlands Cancer Institute
Francien Talens: University Medical Center Groningen, University of Groningen
Jinhyuk Bhin: The Netherlands Cancer Institute
Renske Linstra: University Medical Center Groningen, University of Groningen
Lou Romanens: The Netherlands Cancer Institute
Arkajyoti Bhattacharya: University Medical Center Groningen, University of Groningen
Stacey E. P. Joosten: Oncode Institute
Ana Moises Silva: The Netherlands Cancer Institute
Nuno Padrao: Oncode Institute
Max D. Wellenstein: Oncode Institute
Kelly Kersten: The Netherlands Cancer Institute
Mart Boo: The Netherlands Cancer Institute
Maurits Roorda: University Medical Center Groningen, University of Groningen
Linda Henneman: The Netherlands Cancer Institute
Roebi Bruijn: The Netherlands Cancer Institute
Stefano Annunziato: The Netherlands Cancer Institute
Eline Burg: The Netherlands Cancer Institute
Anne Paulien Drenth: The Netherlands Cancer Institute
Catrin Lutz: The Netherlands Cancer Institute
Theresa Endres: University of Würzburg, Am Hubland
Marieke Ven: The Netherlands Cancer Institute
Martin Eilers: University of Würzburg, Am Hubland
Lodewyk Wessels: Oncode Institute
Karin E. Visser: Oncode Institute
Wilbert Zwart: Oncode Institute
Rudolf S. N. Fehrmann: University Medical Center Groningen, University of Groningen
Marcel A. T. M. Vugt: University Medical Center Groningen, University of Groningen
Jos Jonkers: The Netherlands Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34000-6

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DOI: 10.1038/s41467-022-34000-6

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