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.

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The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis. -deficient mice were highly resistant to methylcholanthrene-induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged in-deficient mice. The combination of deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy.