Effects of interleukin-1 receptor antagonist on tumor stroma in experimental uveal melanoma.

purposeIn 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.

methodsThe 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.

resultsIn 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) β, 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-β, or VEGF. In contrast, host IL-1β, 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.

conclusionsIL-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.