While the IDO inhibitor therapy synergized with CSF R blocka

While the IDO inhibitor therapy synergized with CSF-1R blockade in the B16-IDO tumor model, it was not as effective as the synergy between T cell checkpoint blockade and CSF-1R blockade. Tumor infiltration of MDSCs might be a result of high levels of IDO expression as recently published (Holmgaard et al., 2015), and thus, IDO inhibitors and CSF-1R blockade potentially target the same immune pathway, whereas the T cell checkpoint blockade and CSF-1R blockade therapies act on different immune components and pathways. Several preclinical studies have suggested that inhibition of CSF-1R signaling may alter the immunologic response of tumor-infiltrating MDSCs and/or tumor-infiltrating macrophages (DeNardo et al., 2011; Mitchem et al., 2013; Mok et al., 2014; Priceman et al., 2010; Pyonteck et al., 2013; Sluijter et al., 2014; Strachan et al., 2013; Xu et al., 2013; Zhu et al., 2014). Mok et al. (2014) targeted CSF-1R signaling using PLX3397 in a murine SM1 melanoma model. PLX3397 treatment depleted more than 80% of tumor-infiltrating macrophages, leading to an increased efficacy of adoptively transferred T cell based therapies. Other studies have shown that CSF-1R blockade therapy reduced the number of MDSCs as well as macrophages in tumor and systemic organs (Priceman et al., 2010; Xu et al., 2013). Using the selective inhibitor of CSF-1R, GW2580, Priceman et al. (2010) demonstrated that CSR-1R signaling regulated recruitment of both MDSCs and M2 macrophages to lung, melanoma, and prostate tumors. In our model, CSF-1R blockade with PLX647 mainly targeted the more abundant MDSCs instead of macrophages, suggesting that the role of CSF-1 may be tumor model-dependent. Different tumor models, genetic backgrounds, or treatments may induce different growth factors or cytokines in the tumor microenvironment. Infiltration and differentiation of myeloid Bicalutamide in tumors is a complex process regulated by multiple pathways, which may lead to differential responses to CSF-1R inhibition (Li et al., 2009; Lin et al., 2008; Sawanobori et al., 2008; Wei et al., 2010). For example, while CSF-1R inhibition in pancreas melanoma and breast models resulted in reduction of macrophage numbers, in a murine glioma model Pyonteck et al. (2013) have shown that blockade of CSF-1R signaling using the small molecule inhibitor BLZ945, favorably reprograms macrophage responses without reducing their numbers. In that study, CSF-1R blockade impaired the tumor-promoting functions of M2 macrophages and led to regression of established tumors. Taken together, these results suggest that CSF-1R signaling can regulate both the number and function of tumor-infiltrating myeloid cells, but these activities may be highly dependent on the tumor type or tissue-specific factors. In conclusion, we describe that blockade of CSF-1R signaling in B16-IDO tumors depletes CD11b+Gr1int MDSCs and reprograms the tumor microenvironment to support antitumor immunity. By decreasing the presence of immunosuppressive CD11b+Gr1int MDSCs in the tumor, PLX647 likely facilitates the intratumoral trafficking of CTLs and their antitumor functions. Furthermore, our studies suggest that MDSC inhibition alone by PLX647 is not sufficient for an efficient antitumor response in the B16-IDO tumor model. An active T cell-mediated immunotherapy is needed for an optimal antitumor effect of PLX647 and thus, the main beneficial effects of PLX647 in the B16-IDO model may be derived from the ability to improve T cell effector functions through the inhibition of intratumoral immunosuppressive MDSCs. These data suggest that CSF-1R may be an effective therapeutic target to reprogram the immunosuppressive microenvironment of human tumors strongly infiltrated with myeloid cells and provide a strong rationale for the development of new therapeutic approaches targeting CSF-1R in combination with other agents.