gw-2580 and Prostatic-Neoplasms

Chronic inflammation is known to be associated with prostate cancer development, but how epithelium-associated cancer-initiating events cross talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) occurring intraprostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1(+) CD11b(+) cells, but not those isolated from the spleen of the same tumor-bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, the loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf1 and Il1b, two genes known to induce MDSC expansion and immunosuppressive activities. Treatment of Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epithelium-associated tumor-initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression.

Topics: Animals; Anisoles; Arginase; CD11b Antigen; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Epithelium; Immune Tolerance; Inflammation; Interleukin-1beta; Lymphocyte Activation; Macrophage Colony-Stimulating Factor; Male; Mice; Mice, Transgenic; Myeloid Cells; Nitric Oxide Synthase Type II; Prostate; Prostatic Neoplasms; PTEN Phosphohydrolase; Pyrimidines; Receptors, Chemokine; Signal Transduction; Spleen; T-Lymphocytes; Up-Regulation

Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b(+)F4/80(+) tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b(+)Gr-1(lo)Ly6C(hi) mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti-VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.

Topics: Animals; Anisoles; Carcinoma, Lewis Lung; Cell Line, Tumor; Cell Movement; Lung Neoplasms; Macrophages; Male; Matrix Metalloproteinase 9; Melanoma; Mice; Mice, Inbred C57BL; Myeloid Cells; Neoplasm Transplantation; Neovascularization, Pathologic; Prostatic Neoplasms; Pyrimidines; Rats; Receptor, Macrophage Colony-Stimulating Factor; Signal Transduction; Skin Neoplasms; Vascular Endothelial Growth Factor Receptor-2