Tumor NLRP3-Derived IL-1β Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression

Abstract

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. <i>In vivo</i>, using B16F10 melanoma, OLT1177 effectively reduced tumor progression (<i>p</i>< 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% (<i>p</i><0.01) and <i>II6</i> expression by 53% (<i>p</i><0.05). Disruption of tumor-derived NLRP3, either pharmacologically or genetically, reduced STAT3 signaling in bone marrow cells. In PMN-MDSCs isolated from tumor-bearing mice treated with OLT1177, we observed significant reductions in immunosuppressive genes such as <i>Pdcd1l1</i>, <i>Arg1</i>, <i>Il10</i> and <i>Tgfb1</i>. In conclusion, the data presented here show that the inhibition of NLRP3 reduces IL-1β induction of pSTAT3(Y705) preventing expression of immunosuppressive genes as well as activity in PMN-MDSCs.