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

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.

SUBMITTER: Zimmerli D

PROVIDER: S-EPMC9630413 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

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

Nature communications 20221102 1

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 over ...[more]

PMID: 36323660

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Project description:BackgroundIncreasing studies have reported that oncogenes regulate components of the immune system, suggesting that this is a mechanism for tumorigenesis. Aurora kinase A (AURKA), a serine/threonine kinase, is involved in cell mitosis and is essential for tumor cell proliferation, metastasis, and drug resistance. However, the mechanism by which AURKA is involved in immune response regulation is unclear. Therefore, this study aimed to investigate the role of AURKA in immune regulation in triple-negative breast cancer (TNBC).MethodsPeripheral blood mononuclear cells (PBMCs) were co-cultured with TNBC cells. The xCELLigence Real-Time Cell Analyzer-MP system was used to detect the killing efficiency of immune cells on TNBC cells. The expression of immune effector molecules was tested by quantitative real-time polymerase chain reaction (qRT-PCR) to evaluate immune function. Furthermore, to validate AURKA-regulated immune response in vivo, 4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice. The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry.ResultsDownregulation of AURKA in TNBC cells increased immune response by activating CD8+ T cell proliferation and activity. Nuclear rather than cytoplasmic AURKA-derived programmed death-ligand 1 (PD-L1) expression was independent of its kinase activity. Mechanistic investigations showed that nuclear AURKA increased PD-L1 expression via an MYC-dependent pathway. PD-L1 overexpression mostly reversed AURKA silencing-induced expression of immune effector molecules, including interleukin- (IL-2), interferon-γ (IFN-γ), and perforin. Moreover, AURKA expression was negatively correlated with the enrichment and activity of tumor-infiltrating CD8+ T cells in 4T1 engrafted BALB/c mouse model.ConclusionsNuclear AURKA elevated PD-L1 expression via an MYC-dependent pathway and contributed to immune evasion in TNBC. Therapies targeting nuclear AURKA may restore immune responses against tumors.

Dataset Information

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

Publications

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

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