PTP inhibition improves the macrophage anti-tumor immune response and the efficacy of chemo- and radiotherapy [GeoMX profiling]
Traditional anti-cancer therapies induce tumor cell death and subsequent release of Damage Associated Molecular Patterns (DAMPs) that activate the innate inflammatory response. Paradoxically, after treatment macrophages often adopt a pro-wound healing phenotype that contributes to cancer progression. We found that tumor cells upregulate the expression of Pros1 in areas proximal to cell damage. Tumor-secreted Pros1 binds to the macrophage Mer receptor, effectively limiting responsiveness to DAMPs by preventing Toll Like Receptor (TLR) signal transduction. Pharmacologically inhibiting PTP1b signaling downstream of Mer rescues the pro-inflammatory response even in the presence of Pros1. Combining PTP inhibition with traditional therapeutics, like chemo- or radiotherapy, rescues the innate immune response to DAMPs, increases immune infiltration, and causes 40-90% reductions in tumor growth in multiple treatment refractory preclinical models. Our findings suggest a novel use for PTP1b inhibitors as a tumor agnostic means of improving the efficacy of some of the most widely used anti-cancer therapeutic agents. Overall design: GeoMX profiling of PanCK+ and CD45+ areas of B16F10 syngeneic murine tumors treated with PBS (iq, qd), cisplatin (5mg/kg, ip, once daily for three days), BVT948 (10mg/kg, ip, qd) or their combination collected 6 days after the start of the treatment. Regions of interest were picked based on gH2Ax expression, Pros1 expression, and Mer-Stat1 colocalization positive and negative areas. PanCK+ (melanoma fraction) and CD45+ (immune fraction) sections were manually determined using GeoMx DSP instruments and fluorescent antibodies against these proteins.