The Immunosuppressive Microenvironment in BRCA1-IRIS–Overexpressing TNBC Tumors Is Induced by Bidirectional Interaction with Tumor-Associated Macrophages
Authors: Eman Sami
Bibbin T Paul
James A Koziol
Wael M ElShamy
Journal: Cancer Research (2020)
Discipline: CLINICAL MEDICINE
Keywords: Tumor-associated macrophages; TNBC progression; BRCA1-IRIS; GM-CSF; HIF1α
Affiliations: Breast Cancer Program, San Diego Biomedical Research Institute, San Diego, California., Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut., Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California., Breast Cancer Program, San Diego Biomedical Research Institute, San Diego, California. .

Abstract:  Tumor-associated macrophages (TAM) promote triple-negative breast cancer (TNBC) progression. Here, we report BRCA1-IRIS-overexpressing (IRISOE) TNBC cells secrete high levels of GM-CSF in a hypoxia-inducible factor-1α (HIF1α)- and a NF-κB-dependent manner to recruit macrophages to IRISOE cells and polarize them to protumor M2 TAMs. GM-CSF triggered TGFβ1 expression by M2 TAMs by activating STAT5, NF-κB, and/or ERK signaling. Despite expressing high levels of TGFβ1 receptors on their surface, IRISOE TNBC cells channeled TGFβ1/TβRI/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 TGFβ1. Coinjecting macrophages with IRISOE TNBC cells induced earlier metastasis in athymic mice accompanied by high levels of circulating GM-CSF and TGFβ1. 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+/PD-1+ cytotoxic T cells and more CD25+/FOXP3+ 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. 

Retracted: No

PubPeer comments:
 At least four major issues with Figure 1: I and K in Cancer Research paper: 1) Image duplication: IHC image I and K are presented as two different cell lines, but are duplicates. 2) IHC image I (or K) is flipped in both x and y directions. 3) IHC images I and K have different color intensities. 4) Black blue spots (indicated by black arrows) in I disappear in K. Black spot (indicated by green arrow) in K disappear in I. There are even more spots to be indicated. Consequently, for Fig.1 M, the data come into question as they are partly based on images I and K. ![file] Figure 3 F and G: Why is it so that the MDA-MB-468 controls (shCtrl) grow slightly faster than the MDA-MB-231 (shCtrl) tumours (see vertical line set at day 25)? It is known from the literature that MDA-MB-231 tumours grow more rapidly than MDA-MB-468 tumours (e.g. as seen below in black frame). ![file] ,