AUTHOR=Tengesdal Isak W. , Dinarello Alberto , Powers Nicholas E. , Burchill Matthew A. , Joosten Leo A. B. , Marchetti Carlo , Dinarello Charles A. 

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.661323

DOI=10.3389/fimmu.2021.661323

ISSN=1664-3224

ABSTRACT=<p>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. <italic>In vivo</italic>, using B16F10 melanoma, OLT1177 effectively reduced tumor progression (<italic>p</italic>&lt; 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% (<italic>p</italic>&lt;0.01) and <italic>II6</italic> expression by 53% (<italic>p</italic>&lt;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 <italic>Pdcd1l1</italic>, <italic>Arg1</italic>, <italic>Il10</italic> and <italic>Tgfb1</italic>. 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.</p>