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  • Furthermore the Langerhans cell infiltrate in skin biopsies


    Furthermore, the Langerhans cell infiltrate in skin biopsies from RG7155-treated patients will be analyzed since keratinocyte derived IL-34 was identified as their survival factor (Greter et al., 2012). Microglia, the other macrophage population regulated by neural progenitor and glial cell-derived IL-34, was not affected in the RG7155-treated monkey kn to nm receptor tissue (data not shown). Currently, it is unclear whether, in the context of glioblastoma accompanied with an impaired blood-brain barrier, a sufficient amount of antibody would reach the tumor. Proneural glioblastoma (GBM) might be a promising avenue for further development of RG7155 since this resembles a tumor type in which inhibition of CSF-1R resulted in TAM re-education instead of depletion (Pyonteck et al., 2013). Furthermore, the presence of IL-34 has been shown to inhibit GBM cell line proliferation via its second receptor protein-tyrosine phosphatase (Nandi et al., 2013), which we expect to be similarly elevated upon RG7155 administration as CSF-1. Hence, the use of a CSF-1R inhibitor in GBM might not only indirectly effect tumor growth by reducing TAM suppressive function and re-educating their antitumoral state, but also directly target GBM tumor cells via IL-34. Targeting of macrophages is a promising therapeutic approach, considering their role in mediating resistance to cancer therapies. TAMs have been shown to blunt chemotherapy-induced antitumor responses by secreting chemoprotective factors such as MMP-9 and cathepsins (De Palma and Lewis, 2013, Shree et al., 2011). A previous report of small-molecule CSF-1R inhibitors used for macrophage depletion in PyMT mice (DeNardo et al., 2011) described kn to nm receptor increased CD8+ T cell levels, but only when administered in combination with chemotherapy. In contrast, our 2G2 antibody mediated macrophage depletion and relatively increased CD8+ T cells and NK cells in tumors when delivered in monotherapy. These differences might be attributed to the dominating role of macrophages in the MC38 and MCA1 models employed for our studies or to differences in the CSF-1R inhibitors used. The latter is more likely since an increase of CD8+ T cells has been observed in PyMT using another CSF-1R small-molecule inhibitor, BLZ945 (Strachan et al., 2013). The immunosuppressive function of TAMs is well documented (Cavnar et al., 2013) and was also confirmed here for the CSF-1-dependent human in vitro-differentiated and ex vivo-isolated murine TAMs. Most strikingly, we report that targeting of CSF-1R results in a higher CD8/CD4 T cell ratio in tumor lesions in the majority of the cancer patients analyzed. However, we were unable to identify a correlation between the grade of macrophage depletion or the severity of basal macrophage infiltrate and the changes in the T cell composition, due to the low number of patients analyzed. Of note, patients with a tumor type in which macrophages have been associated with its etiopathology, such as mesothelioma (Yang et al., 2008), were among those patients that showed the most pronounced changes in lymphocyte infiltrate. Taken together, these observations provide rationale for future testing of combinations of RG7155 with currently available immunostimulatory therapies, such as sipuleucel-T and anti-CTLA-4 (Chen and Mellman 2013). Accordingly, an obstacle limiting the efficacy of such immune-activating therapies may well be the presence of an immunosuppressive myeloid infiltrate, which now can be targeted by RG7155. While some studies have suggested an antitumorigenic activity of TAM subpopulations (Weiskopf et al., 2013, Beatty et al., 2011), targeting of the strong immunosuppressive function of TAMs at the cost of their potential tumoricidal activity is expected to be therapeutically beneficial, given that T cells are considered to be the more powerful effector cells, due to their capability to expand by proliferation.
    Experimental Procedures
    Author Contributions