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. 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.

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

“…However, the molecular mechanism through which driving MDSC mobilization into inflamed liver remains elusive. Upon NLRP3 activation, the inactive IL-1β precursor is processed by caspase-1 to active, mature IL-1β, which could induce cytokines associated with MDSC expansion such as IL-6 and IL-8 (30). A recent study suggested that IL-25 is highly expressed in both the human and mouse liver and plays a critical function in maintaining the homeostasis and limiting local inflammation through recruiting MDSC (31).…”

STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

“…In the last decade, in vitro studies revealed connections between HIF1α and other transcription factors among which Signal Transducer and Activator of Transcription 3 (STAT3) emerged as an important modulator of hypoxia/HIF1α activity (Pawlus et al ., 2014; Grillo et al ., 2020). STAT3 is a component of the JAK/STAT pathway that has been claimed to control cell proliferation in cancer and pluripotent stem cells, via their transcriptional and metabolic regulation (Avalle et al ., 2017; Tengesdal et al ., 2021; Carbognin et al ., 2016; Betto et al ., 2021, Tesoriere et al, 2021).…”

Inflammasomes in Cancer Progression and Anti-Tumor Immunity

“…Besides TAMs, PDAC tumor cells also activate the Nlrp3 inflammasome and act as a prominent source of IL-1β ( Das et al, 2020 ). Tumor-derived IL-1β might also act via an IL-6-STAT3 inflammatory loop to expand MDSCs and induce immunosuppression ( Tengesdal et al, 2021a ). Tengesdal et al have demonstrated this using the B16-F10 melanoma model and further showed that Nlrp3 inhibition with dapansutrile (OLT1177) abrogated the expression of immunosuppressives genes in PMN-MDSC and enhanced anti-tumor immunity in vivo ( Tengesdal et al, 2021b ).…”