Multiscale modeling uncovers macrophage infiltration and TNF-α signaling networks for targeting in inflammatory breast cancer tumor emboli

Abstract Inflammatory breast cancer (IBC) tumors are characterized by diffuse clusters of cells found in dermal tissue and lymphatic vessels, known as tumor emboli. Thus, IBC needs a novel treatment because it is the most aggressive breast cancer subtype. We hypothesized that the interaction between tumor emboli and the tumor immune microenvironment (TiME) fosters survival signaling, leading to the aggressiveness of the IBC. In this study, ex vivo tumor emboli were generated from patient-derived cell lines cultured in a lymphatic-like environment, which was compared to 2D monolayer cultures, revealing upregulation of TNFR signaling networks, CXCL8, and immune cell chemotaxis genes. Spatial immunophenotyping of IBC patient tumors demonstrated high levels of CD163+ tumor-associated macrophages (TAMs). Furthermore, intravital imaging of CX3cr1 GFP mice confirmed macrophage movement toward tumor cell clusters. Finally, targeting macrophage-associated TNF-α-signaling using Birinapant, a SMAC mimetic, inhibited the tumor emboli phenotype in vivo, identifying Birinapant as a potential therapeutic agent to disrupt this signaling axis.