Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer that displays profound cancer stem cell (CSC) and mesenchymal features that promote rapid metastasis. Another hallmark of IBC is high infiltration of M2 tumor-associated (immune-suppressing) macrophages (TAM). The molecular mechanism that drives these IBC phenotypes is not well understood. Using patient breast tumor specimens, breast cancer cell lines, and a patient-derived xenograft (PDX) model of IBC, we demonstrate that IBC strongly expresses IL-8 and GRO chemokines that activate STAT3, which promotes development of high levels of CSC-like cells and a mesenchymal phenotype. We also show that IBC expresses high levels of many monocyte recruitment and macrophage polarization factors that attract and differentiate monocytes into tumor-promoting, immune-suppressing M2-like macrophages. The M2 macrophages in turn were found to secrete high levels of IL-8 and GRO chemokines, thereby creating a feed-forward chemokine loop that further drives an IBC epithelial-to-mesenchymal transition. Our study uncovers an intricate IBC-initiated autocrine-paracrine signaling network between IBC cells and monocytes that facilitates development of this highly aggressive form of breast cancer.

Introduction Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data demonstrates strong activation of the PI3K/mTOR and JAK/STAT pathways, expression of inflammatory cytokines and tumor associated macrophages (TAMs). Methods Archival tumor tissue from three disease types (IBC treated with neoadjuvant chemotherapy (NAC) (n=45); invasive ductal carcinoma (IDC) treated with NAC (n=24; ‘treated IDC’); and untreated IDC (n=27; ‘untreated IDC’)) was analyzed for the expression of biomarkers pS6 (mTOR), pJAK2, pSTAT3, IL6, CD68 (monocytes, macrophages) and CD163 (TAMs). Surrounding non-tumor tissue was also analyzed. Results Biomarker levels and surrogate activity by site-specific phosphorylation were demonstrated in the tumor tissue of all three disease types but were highest in IBC and treated IDC and lowest in untreated IDC for pS6, pJAK2, pSTAT3 and IL6. Of 37 IBC patients with complete biomarker data available, 100% were pS6 positive and 95% were pJAK2 positive. In non-tumor tissue, biomarker levels were observed in all groups but were generally highest in untreated IDC and lowest in IBC, except for JAK2. Conclusions IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, suggesting a potential mechanism of resistance after NAC. Biomarker levels in surrounding non-tumor tissue suggest that the stroma may be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of both pS6 and pJAK2 in IBC may support dual targeting of mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combinatorial targeted therapies in IBC.

Most patients with non–small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)–induced cell death (NICD) of P2X7 receptor (P2X7R)–expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono–adenosine 5′-diphosphate (ADP)–ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R + CD8 T cell subset in human lung adenocarcinomas. In vitro, P2X7R + CD8 T cells were susceptible to ART1-mediated ADP-ribosylation and NICD, which was exacerbated upon blockade of the NAD + -degrading ADP-ribosyl cyclase CD38. Last, in murine NSCLC and melanoma models, we demonstrate that genetic and antibody-mediated ART1 inhibition slowed tumor growth in a CD8 T cell–dependent manner. This was associated with increased infiltration of activated P2X7R + CD8 T cells into tumors. In conclusion, we describe ART1-mediated NICD as a mechanism of immune resistance in NSCLC and provide preclinical evidence that antibody-mediated targeting of ART1 can improve tumor control, supporting pursuit of this approach in clinical studies.

PurposeThe accumulation of wound fluid known as seroma in the chest cavity following breast surgery is a common occurrence that can persist for many weeks. While the pro-inflammatory composition of seroma is well established, there has been remarkably little research to determine whether seroma contains pro-oncogenic factors, and whether this is influenced by previous malignant disease.MethodsWe developed a clinical trial in which we obtained post-surgical seroma fluids from women with benign or malignant disease 1 or 2 weeks following lumpectomy or mastectomy. We conducted an analysis of more than 80 different cytokines, chemokines and growth factors.ResultsWe found that surgical cavity seroma from breast cancer patients has a higher expression of key tumor-promoting cytokines and lower expression of important tumor-inhibiting factors when compared to benign lesions from non-cancer patients. Patients with high body mass index also had higher levels of leptin regardless of malignancy.ConclusionsWe conclude that the breast post-surgical tumor cavity contains factors that are pro-inflammatory regardless of malignant or benign disease, but in malignant disease there is significant enrichment of additional pro-oncogenic chemokines, cytokines and growth factors, and reduction in tumor-inhibiting factors. These results are consistent with tumor conditioning of surrounding normal stromal tissue and creation of a pro-oncogenic environment that persists long after surgical removal of the tumor.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1260-8) contains supplementary material, which is available to authorized users.

<p>TS1 describes the characteristics of the cell lines used in this study, including hormone receptor status and type of breast cancer. TS2 lists the antibodies used and the method by which immunohistochemistry stained breast cancer specimens were scored. TS3 describes the levels of IL8, Jak2, P-Ja2, STAT3, P-STAT3 and monocyte macrophages (CD68, CD163) in normal breast tissue and IBC specimens. TS4 lists the expression levels of 80 cytokines, chemokines and growth factors in the conditioned media from SUM149 cells. Data were obtained from at least three independent studies. TS5 lists the sequences of siRNAs that were used for gene silencing in this study. TS6 lists the primer sequences and the genes targeted for qPCR studies carried out.</p><p></p>