Effects of Interleukin-1 Receptor Antagonist on Tumor Stroma in Experimental Uveal Melanoma

PURPOSE. In contrast to many malignancies showing evidence that interleukin-1 (IL-1) promotes progression through effects on tumor vascularity and myeloid suppressor cell populations, in uveal melanoma there is evidence that IL-1 can inhibit progression. METHODS. The effects of the IL-1 receptor antagonist IL-1ra against the aggressive/invasive MUM2B and the nonaggressive/noninvasive OCM1 uveal melanoma models were examined in vitro and in vivo in mouse xenografts. Vascularity and myeloid suppressor cell populations and their regulators were assessed. RESULTS. In vitro, IL-1, and IL-1ra did not affect the proliferation of the uveal melanoma cells or their production of IL-1, IL-6, transforming growth factor (TGF) beta, or VEGF. In vivo, IL-1ra treatment resulted in substantial growth inhibition of MUM2B tumors; less inhibition was observed against OCM1 tumors. Periodic acid-Schiff loops and CD11b(+) macrophages within the tumor stroma decreased in vivo; CD31(+) blood vessels were not altered. IL-1ra treatment in vivo did not affect tumor-derived IL-1, IL-6, TGF-beta, or VEGF. In contrast, host IL-1 beta, IL-6, and tumor necrosis factor decreased. Host VEGF was not altered. Intratumoral IL-12(p40) and CXCL10, markers of host M1 polarization, increased, and intratumoral arginase and CD206, markers of myeloid-derived suppressor cells (MDSC) and M2 macrophage polarization, decreased. IL-1ra treatment in vivo also reduced splenic CD11b(+) Gr1(+) MDSC. CONCLUSIONS. IL-1 may play a role in promoting uveal melanoma progression. Inhibiting IL-1 with IL-1ra inhibits tumor growth in vivo but not in vitro. Tumor stroma is modified, myeloid suppressor cells are reduced, and M1 macrophage polarization is increased in vivo. (Invest Ophthalmol Vis Sci. 2011; 52: 5529-5535) DOI: 10.1167/iovs.10-6331