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.

Oncogenic drivers dictate immune control of acute myeloid leukemia

“…However, we believe that Myc activity has not previously been linked to the expression of antigen presentation machinery. Interestingly, recent studies have described a direct role for Myc in the repression of interferon response genes in Nras G12D driven models of pancreatic ductal adenocarcinoma and triple negative breast cancer 53 , 54 . It is tempting to speculate that MYC-mediated suppression of mutant RAS driven activation of interferon signaling may be an unappreciated aspect of this cooperative oncogenic relationship that is exploited by cancers of all cell lineages.…”

Immune checkpoints expression patterns in early-stage triple-negative breast cancer predict prognosis and remodel the tumor immune microenvironment

“…A high number of TILs predicts favorable prognosis and pathological complete response in TNBC and HER2-enriched BC subtypes ( 61 ). TNBC patients with sparse or unresponsive tumor-infiltrating lymphocytes have limited efficacy of ICIs treatment ( 62 ). In the present study, patients with low IRS tended to have a higher infiltrating of CD8 T cells, activated NK cells and M1 Macrophages, which indicated that these patients had a better long-term survival than patients with high IRS and might be more suitable for ICI therapies.…”

Oncogenic drivers dictate immune control of acute myeloid leukemia

“…However, we believe this is the first time that Myc activity has been linked to the expression of antigen presentation machinery. Interestingly, recent studies have described a direct role for Myc in the repression of interferon response genes in Nras G12D driven models of pancreatic ductal adenocarcinoma and triple negative breast cancer [55, 56]. It is tempting to speculate that Myc-mediated suppression of mutant RAS driven activation of interferon signaling may be an unappreciated aspect of this cooperative oncogenic relationship that is exploited by cancers of all cell lineages.…”