PTP Inhibition Improves the Macrophage Antitumor Immune Response and the Efficacy of Chemo- and Radiotherapy

Traditional anticancer 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, rather than proinflammatory, phenotype and contribute to cancer progression. We found that in areas proximal to DAMP release, tumor cells upregulate the expression of Pros1. Tumor-secreted Pros1 binds to the macrophage Mer receptor, consequently limiting responsiveness to DAMPs by preventing Toll-like receptor signal transduction. Pharmacological inhibition of PTP1b signaling downstream of Mer rescued the proinflammatory response, even in the presence of Pros1. Combining protein tyrosine phosphatase (PTP) inhibition with traditional therapeutics, such as chemo- or radiotherapy, rescued the innate immune response to DAMPs, increased immune infiltration, and resulted in a 40% to 90% reduction in tumor growth in multiple treatment-refractory preclinical models. Our findings suggest using PTP1b inhibitors may be a tumor agnostic means of improving the efficacy of some of the most widely used anticancer therapeutic agents.