Abstract 4403: Combined antagonism of the IL-4R and IKKα inhibits melanoma tumor growth in immunocompetent mice

Abstract

Abstract With over 8500 deaths each year in the USA, malignant melanoma is the deadliest of all skin cancers. Constitutive activation of the nuclear factor kappa B (NF-κB) is common in melanoma, promoting tumor growth, survival and metastasis. In light of its role in tumorigenesis, targeting of the NF-κB pathway has been considered a possible therapeutic option for the treatment of melanoma. However, NF- αB activation is critical for the development, survival, migration and function of immune cells. We hypothesized that systemic inhibition of the activation of NF-κB might have a deleterious effect on the tumor immune response. Melanoma bearing C57BL/6 mice received 50 mg/kg of BMS-345541, a selective inhibitor of the inhibitor of αB kinase (IKKα), twice daily. Tumors, spleens and bone marrow were harvested at different time points and analyzed by flow cytometry for leukocyte composition and cytokine production. Intracellular cytokine staining revealed an early induction of Interleukin-4 (IL-4) within the myeloid and B cell components of the tumor, as a result of BMS-345541 treatment. The production of IL-4 by these cells suggests an early switch to a tumor promoting T helper 2 (Th2) and M2 driven immune response, which may counteract the anti-tumor effect of IKKα inhibition by generating a pro-tumorigenic microenvironment. These results, in part, explain the modest delay in tumor growth demonstrated. IL-4 receptor (IL-4R) expression on human melanoma cells has been previously documented; however the effects of IL-4 on these cells have generated contradictory reports. IL-4R signaling has been shown to either inhibit growth of tumor cells in vitro or to promote survival of tumor cells. In C57Bl/6 mice bearing a murine melanoma, BMS345541 (75 mg/kg bid) was given in combination with 100 µg of IL-4R blocking antibody on day 4 and day 12 of treatment. This combination significantly inhibited tumor growth compared to BMS345541 treatment alone. These data suggest an important role for IL-4 in promoting melanoma growth in vivo. Dual targeting of IL-4R and NF-κB signaling pathways neutralizes the tumor promoting immune component. Currently, IL-4R antagonists are in clinical trials for the treatment of asthma, which makes the translational prospects of this study extraordinarily viable. We are grateful for support from the NCI (CA116021-07, 5T32CA119925-03) and the Department of Veterans Affairs for these studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4403. doi:1538-7445.AM2012-4403