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. In vivo, using B16F10 melanoma, OLT1177 effectively reduced tumor progression (p< 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% (p<0.01) and II6 expression by 53% (p<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 Pdcd1l1, Arg1, Il10 and Tgfb1. 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.
Highlights
An evolving understanding of malignant tumor progression reveals that tumors evade the immune system through several mechanisms including NK and T cell exhaustion [1, 2], regulatory T cell induction [3, 4], expression of inhibitory receptors [5], tumor-associated macrophage alterations [6] and recruitment of myeloid-derived suppressor cells (MDSCs) [7]
We investigate whether NOD-like receptor protein 3 (NLRP3)-dependent IL-1b production observed in melanoma cells drives IL-6/STAT3 signaling and whether this influences myeloidderived suppressor cells (MDSCs) activity
We have previously shown that metastatic melanoma cells display constitutively active NLRP3 resulting in spontaneous IL-1b production and release [16]
Summary
An evolving understanding of malignant tumor progression reveals that tumors evade the immune system through several mechanisms including NK and T cell exhaustion [1, 2], regulatory T cell induction [3, 4], expression of inhibitory receptors [5], tumor-associated macrophage alterations [6] and recruitment of myeloid-derived suppressor cells (MDSCs) [7]. MDSCs facilitate tumor immune evasion by inhibiting anti-tumor responses of both T and NK cells as well as induction of regulatory T cells [8,9,10]. IL-1b/IL-6/STAT3 Axis Regulates MDSC Immunosuppression associated inflammation (for example, pro-inflammatory cytokines). Patients with advanced stage melanoma have elevated circulating levels of the proinflammatory cytokines IL‐1b and IL‐6, which correlate with poor prognosis [13, 14]. Inflammatory cytokines such as IL‐1b and IL‐6 have been associated with MDSCs expansion and activity [15, 16]. The molecular mechanisms linking inflammation to MDSCs expansion and immunosuppressive gene regulation remain unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
