The Immunosuppressive Microenvironment in BRCA1-IRIS–Overexpressing TNBC Tumors Is Induced by Bidirectional Interaction with Tumor-Associated Macrophages

Abstract

Tumor-associated macrophages (TAM) promote triplenegative breast cancer (TNBC) progression. Here, we report BRCA1-IRIS-overexpressing (IRISOE) TNBC cells secrete high levels of GM-CSF in a hypoxia-inducible factor-1a (HIF1a)-and a NF-kB-dependent manner to recruit macrophages to IRISOE cells and polarize them to protumor M2 TAMs. GM-CSF triggered TGFb1 expression by M2 TAMs by activating STAT5, NF-kB, and/or ERK signaling. Despite expressing high levels of TGFb1 receptors on their surface, IRISOE TNBC cells channeled TGFb1/TbRI/II signaling toward AKT, not SMAD, which activated stemness/EMT phenotypes. In orthotopic and syngeneic mouse models, silencing or inactivating IRIS in TNBC cells lowered the levels of circulating GM-CSF, suppressed TAM recruitment, and decreased the levels of circulating TGFb1. Coinjecting macrophages with IRISOE TNBC cells induced earlier metastasis in athymic mice accompanied by high levels of circulating GM-CSF and TGFb1. IRISOE TNBC cells expressed low levels of calreticulin (the "eat me" signal for macrophages) and high levels of CD47 (the "do not eat me" signal for macrophages) and PD-L1 (a T-cell inactivator) on their surface. Accordingly, IRISOE TNBC tumors had significantly few CD8 þ /PD-1 þ cytotoxic T cells and more CD25 þ /FOXP3 þ regulatory T cells. These data show that the bidirectional interaction between IRISOE cells and macrophages triggers an immunosuppressive microenvironment within TNBC tumors that is favorable for the generation of immune-evading/ stem-like/IRISOE TNBC metastatic precursors. Inhibiting this interaction may inhibit disease progression and enhance patients' overall survival.Significance: The BRCA1-IRIS oncogene promotes breast cancer aggressiveness by recruiting macrophages and promoting their M2 polarization.

Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights

“…Due to the notable aggressive behaviour of TNBC, existing treatment options have limited or no efficacy against tumour metastasis 44,47 . Recently, Different molecular studies have allowed for the emergence of targeted therapies 48 , whereas others have evolved to explain mechanisms of resistance [49][50][51][52][53] . Several signalling pathways and biomarkers have been shown to be implicated in TNBC progression such as BAX/BCL2, HSP90α, EGFR, VEGF, survivin, CDK1, caspases, mTOR, and Ras/Raf/MEK/ERK 22,[52][53][54][55][56][57][58][59][60] .…”

Comprehensive genomic and immunophenotypic analysis of CD4 T cell infiltrating human triple-negative breast cancer

“…Our study revealed that cytotoxic and memory T cells significantly decreased, whereas regulatory T cells and apoptotic T cells markedly increased in TNBC patients. Tumors infiltrated with polarized regulatory T cells were suggested an immunosuppressive microenvironment and a poorer prognosis of TNBC patients [ 56 , 57 ]. By comparing the profiles of the whole immune cells from TNBC tissue with that from normal breast tissue, we found that although Treg cells increased, but there is no significance (Supplementary Fig.…”

Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

“…GM-CSF BRCA1-IRIS overexpressing TNBC cells secrete high quantities of GM-CSF in an NF-κB and a HIF-1α-dependent manner to induce macrophages to IRIS overexpressing cells and polarize them to pro-tumor TAMs (M2). GM-CSF triggers TGF-β1 expression on TAMs through activating STAT5, NF-κB and/or ERK signaling [71].…”