Fig. 3

Proposed implications of IFNα signaling between IBC tumor and the tumor microenvironment. a During canonical IFNα signaling which often occurs during the first steps of immunosurveillance, dendritic cells and macrophages promote tumor cell killing through release of high levels of IFNα. Dendritic cells have high levels of MHC class I and II as well as co-activators (CD40/CD80) which promote the cytotoxic T cell response against the tumor. Macrophages are often polarized to be more M1-like in this scenario. IFNα promotes increased migration of M1-macrophages to the inflamed tissue to aid in antigen presentation. b Hypothesized alterations due to chronic IFNα signaling. IFNα secreted from the tumor cells may act in an autocrine or paracrine manner. In an autocrine fashion, IFNα binds to the receptors on IBC tumor cells increasing PD-L1 expression and upregulating canonical and non-canonical JAK/STAT signaling. Immune evasion may occur through release of IFNα and the paracrine effect on dendritic cells. We hypothesize that increased levels of IFNα produced in the tumor and secreted into the TME in a chronic manner essentially exhausts dendritic cells inhibiting their capability of simulating cytotoxic T cells while instead the helper T cell population is expanded. Furthermore, regulation of JAK/STAT signaling by IFNα may increase DNA damage resistance through increasing ISG production. Additionally, IBC migration is altered through interaction with macrophages. Tumor-associated macrophages in IBC are shown to enhance RhoC-GTPase activation and JAK/STAT signaling by macrophages makes these cells highly aggressive due to their invasion into the blood vessels and the high rate of angiogenesis in IBC. Fibroblasts and endothelial cells in IBC remain understudied; however, macrophages may have the capability to increase the activation of these cells. Adapted from Lim et al. [8]