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 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 LutzTheresa 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*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

18 Citaten (Scopus)
39 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Artikelnummer6579
Aantal pagina's18
TijdschriftNature Communications
Volume13
DOI's
StatusPublished - dec.-2022

Citeer dit