Combined blockade of IL-4R and IKKβ inhibits melanoma growth in vivo (P2032)

Abstract

Constitutive activation of the nuclear factor kappa B (NF-κB) is common in melanoma, promoting tumor growth and metastasis. Therefore, targeting the NF-κB pathway is a possible therapeutic option. However, NF- κB activity is critical for the development and function of immune cells. Melanoma bearing C57BL/6 mice received BMS-345541, a selective inhibitor of the inhibitor of κB kinase (IKKβ). No difference was observed in tumor size. Tumors were analyzed by flow cytometry and intracellular cytokine staining revealed an early induction of Interleukin-4 (IL-4) within the leukocyte compartment of the tumor, with drug treatment. The production of IL-4 leads to an early switch to a tumor promoting T helper 2 (Th2) driven immune response, counteracting the anti-tumor effect of IKKβ inhibition. IL-4 receptor (IL-4R) expression on human melanoma cells has been documented; however the effects of IL-4 on these cells have generated contradictory reports. In vitro IL-4 delivery did not alter either the proliferative capacity of IL-4R expressing melanoma cell lines or their sensitivity to BMS-345541. In nude mice bearing an IL-4 transduced human A375 melanoma , BMS345541 was given in combination with IL-4R blocking antibody. This combination inhibited tumor growth compared to BMS-345541 treatment alone, similar to previous studies in C57BL/6 mice. IL-4R antagonists are in clinical trials for the treatment of asthma, making the translational prospects of this study extraordinarily viable.