Effects of Interleukin-1 Receptor Antagonist and Chemotherapy on Host–Tumor Interactions in Established Melanoma

Background: Interleukin-1 (IL-1) has been implicated in the vascular and immune suppressor cell responses that promote tumor progression. IL-1, however, has also been shown to inhibit tumor progression by promoting antitumor immune responses and by enhancing the activity of chemotherapy. Materials and Methods: The effects of IL-1 receptor antagonist (IL-1Ra), alone and combined with temozolomide and docetaxel chemotherapy, were examined in vitro and in vivo against microscopic and macroscopic mouse B16 melanoma. Results: IL-1Ra did not demonstrate antitumor activity in vitro, alone or combined with chemotherapy. When administered in vivo at the time when B16 cells were inoculated, IL-1Ra inhibited tumor growth. It did not affect growth when administered after tumors had established and were macroscopic. IL-1Ra increased M1 macrophage polarization and reduced myeloid-derived suppressor cells in mice with macroscopic tumors. Regulatory T-cells, tumor vascularity, and tumor interstitial fluid pressure were not significantly altered. Pre-treatment but not concurrent treatment with IL-1Ra enhanced the antitumor activity of chemotherapy in vivo against macroscopic tumors. Whereas chemotherapy reduced myeloid suppressor cells systemically, chemotherapy increased markers of myeloid suppressor cells intratumorally. These effects were attenuated by pre-treatment with IL-1Ra. Conclusion: The effects of IL-1 and chemotherapy in melanoma are complex. IL-1Ra modifies myeloid suppressor cell populations and may have a role with chemotherapy in the treatment of established melanoma. Interleukin (IL-1) is a mediator of acute and chronic inflammatory conditions as well as a hematopoietin. Both isoforms, IL-1α and IL-1β, have been implicated in the development, growth, invasion, and metastasis of tumors, as well as in host responses that contribute to tumor progression, including angiogenesis and the ability to escape immune surveillance (reviewed in (1)). Malignant melanoma is a refractory malignancy. The chemotherapies currently applied are rarely effective and are limited by toxicity. In experimental models, IL-1 has been shown to be required for melanoma invasiveness, metastasis, and angiogenesis (2, 3). A naturally occurring antagonist, IL-1Ra, competitively blocks IL-1α and IL-1β at the receptor level. IL-1Ra has demonstrated antitumor activity in mouse B16 melanoma and human melanoma xenograft models, and there is interest in applying IL-1Ra clinically (4-6). As IL-1 has also been implicated in the clinical toxicity of several chemotherapeutics, combining IL-1Ra with chemotherapy has also been suggested to improve treatment outcome (7-10). The antitumor activity of IL-1Ra has been demonstrated in mouse melanoma models when administered at the time of tumor implantation to inhibit invasion, angiogenesis, and/or metastasis (4-6). The effects of IL-1Ra on macroscopic melanoma tumors, where abnormal vascularity and immune escape mechanisms are present, have not been reported. Although IL-1 has been implicated in tumor angiogenesis and in the adverse effects of chemotherapy, IL- 1 has also been reported to improve the cytotoxic effects of chemotherapy in vivo, an effect attributed to vascular effects that result in an increase in intratumoral chemotherapy concentration (11, 12). Furthermore, IL-1 has been shown to directly sensitize tumors to the cytotoxic effects of several cytotoxic chemotherapeutics (13). IL-1Ra is immunosuppressive, and although IL-1 can suppress antitumor immune responses by stimulating of M2-polarized macrophages and myeloid derived suppressor cells (MDSC) (14, 15), IL-1 can potentially promote antitumor immune responses by activating M1 macrophages and dendritic cells, and attenuating FoxP3 + regulatory T (T-reg) cells (16, 17). In fact, IL-1 has demonstrated antitumor activity in mice with macroscopic B16 melanoma, an effect attributed to its ability to activate immune effector mechanisms (18). Human recombinant IL-1Ra (hrIL-1Ra) is used clinically to treat patients with rheumatoid arthritis and has been shown to inhibit B16 melanoma metastases when administered at the