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

Autor: Nicholas E. Powers, Leo A. B. Joosten, Alberto Dinarello, Charles A. Dinarello, Matthew A. Burchill, Carlo Marchetti, Isak W. Tengesdal
Rok vydání: 2021
Předmět:
STAT3 Transcription Factor
interleukin-1β
medicine.medical_treatment
Interleukin-1beta
Immunology
Melanoma
Experimental
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
Inflammation
Immune system
NLRP3
Cell Line
Tumor
NLR Family
Pyrin Domain-Containing 3 Protein
Nitriles
Immune Tolerance
medicine
Animals
Humans
Immunology and Allergy
Melanoma
Original Research
Mice
Knockout
Interleukin-6
Chemistry
Myeloid-Derived Suppressor Cells
Models
Immunological
Immunosuppression
RC581-607
medicine.disease
Tumor Burden
Mice
Inbred C57BL
Interleukin 10
Pyrimidines
medicine.anatomical_structure
Tumor progression
signal transducer and activator of transcription 3
Cancer research
Myeloid-derived Suppressor Cell
Pyrazoles
Bone marrow
Immunologic diseases. Allergy
medicine.symptom
Signal Transduction
Zdroj: Frontiers in Immunology, 12
Frontiers in Immunology
Frontiers in Immunology, Vol 12 (2021)
ISSN: 1664-3224
Popis: 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% (pII6expression by 53% (pPdcd1l1,Arg1,Il10andTgfb1. 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.
Databáze: OpenAIRE
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