473 An IL-1a producing dermal macrophage enhances adaptive immunity to a broad group of tumors in skin

Abstract

IL-1a and IL-1b are the oldest members of the growing IL-1 family of molecules. Mice deficient in IL-1b are viable and are grossly indistinguishable from WT mice. However, they are uniquely effective at rejecting malignant tumor cell lines that grow readily in syngeneic mice. Significant growth reduction of tumors formed by EL4 lymphoma, B16 melanoma, and Lewis Lung carcinoma cells implanted in the skin of IL-1b-/- were all observed, and in many cases tumors grew initially and then regressed completely. These latter mice remained completely resistant to subsequent implantation of tumor cell lines, even at very high numbers. Surprisingly, tumors grew unimpeded in IL-1a-/- and IL-1R-/- mice at a rate indistinguishable from tumors in WT mice. Additional studies demonstrated that antibody depletion of T cells from IL-1b-/- mice completely abrogated the tumor resistance, and that the tumor resistance could be partially mimicked in WT mice with a blocking antibody to IL-1b. Interestingly, the IL-1b-/- tumor resistance effect required the presence of IL-1a. Bone marrow chimera studies indicated that the tumor resistance effect required type I IL-1R to be present on T cells, but also showed that the relevant IL-1b-/- cell mediating the effect produced IL-1a, was not bone marrow derived, and was radioresistant. We speculated that the responsible cell meeting these criteria might be a dermal macrophage, and thus treated mice intradermally with chlodronate, which very effectively depletes macrophages in this setting. Injection of clodronate at day 2 after tumor implantation, and then weekly thereafter, completely abrograted the protective anti-tumor affect in IL-1b-/- mice. Thus, IL-1a, in the absence of IL-1b, appears to have strong stimulatory affect on the adapative immune system that can be harnessed for anti-tumor immunity. Combining antibodies to IL-1b with checkpoint inhibitor antibodies to enhance tumor immunity is a rational goal.