p140Cap overexpression in Balb-neuT HER2 breast cancer transgenic mice

In HER2-positive breast cancer patients the adaptor protein p140Cap correlates with increased patient survival and decreased probability to develop metastasis. Causally, p140Cap negatively regulates in vitro and in vivo breast tumor properties. Here we show that p140Cap status correlates with a rewiring of the tumor immune microenvironment, with an increased presence of tumor-infiltrating lymphocytes (TILs) in human breast cancers and an inverse correlation with inflammatory hallmarks. Preclinical syngeneic p140Cap models show a significant increase of CD8+ T-Lymphocytes, NK cells and M1-macrophages in p140Cap tumors, a reduced mobilization and a decreased recruitment of G-CSF-dependent Myeloid-Derived Suppressor Cells (MDSC), with a specific reduction in G-CSF mRNA and protein levels. Indeed, p140Cap impacts on the G-CSF axis by reducing the fraction of Tumour-Initiating Cells (TICs) that exhibit an enhanced G-CSF production. Interestingly, p140Cap affects the TIC compartment by limiting the active ß-Catenin intracellular pool, stabilizing the destruction complex. These findings identify a novel role of p140Cap in preventing the development of an immunosuppressive tumor promoting microenvironment in Breast Cancer. Overall design: Three Balb-NeuT mice (Mock 1-3, Rovero et al. J. Immunol. 165, 5133–5142, 2000) were compared with respect to three Balb-NeuT mice overexpressing p140Cap (p140 1-3)