azd-1480 and Melanoma

Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1β drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL-6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1β specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1β/IL-6/STAT3 axis, we suppressed IL-1β-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor.

Topics: Animals; Cell Line, Tumor; Humans; Immune Tolerance; Interleukin-1beta; Interleukin-6; Melanoma; Melanoma, Experimental; Mice, Inbred C57BL; Mice, Knockout; Models, Immunological; Myeloid-Derived Suppressor Cells; Nitriles; NLR Family, Pyrin Domain-Containing 3 Protein; Pyrazoles; Pyrimidines; Signal Transduction; STAT3 Transcription Factor; Tumor Burden

AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system. These data indicate that systemic targeting of the JAK/STAT pathway by JAK1/2 inhibition can have divergent effects on tumor growth and anti-tumor immune responses.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Female; Humans; Janus Kinase 2; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Myeloid Cells; Pyrazoles; Pyrimidines; Random Allocation; Signal Transduction; Xenograft Model Antitumor Assays