Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response

Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy, however the mechanisms underlying therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumor-associated macrophages by colony-stimulating factor-1 receptor (CSF-1R) blockade in the K14cre;Cdh1(F/F);Trp53(F/F) transgenic mouse model for breast cancer stimulates intratumoral type I interferon (IFN) signaling which enhances the anti-cancer efficacy of platinum-based chemotherapeutics. Notably, anti-CSF-1R treatment also increased intratumoral expression of type I IFN-stimulated genes in cancer patients, confirming that CSF-1R blockade is a powerful strategy to trigger an intratumoral type I IFN response. By inducing an inflamed, type I IFN-enriched tumor microenvironment and by further targeting immunosuppressive neutrophils during cisplatin therapy, anti-tumor immunity was activated in this poorly immunogenic breast cancer mouse model. These data illustrate the importance of breaching multiple layers of immunosuppression during cytotoxic therapy to successfully engage anti-tumor immunity in breast cancer.