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  • In our model CSF R blockade

    2019-07-04

    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 fk 506 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 fk 506 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.
    Conflict of Interest Statement
    Funding This work was in part supported by the NIH grant R01CA56821, the NIH/NCI Cancer Center Support Grant P30CA008748, Swim Across America, Ludwig Cancer Research, and Breast Cancer Research Foundation. RBH is the recipient of postdoctoral fellowships through The Danish Cancer Society (R56-A2943-12-S2) and The Carlsberg Foundation (CF14-0224), Denmark.
    Author Contributions
    Acknowledgement