Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion
Isak W. Tengesdal,Isak W. Tengesdal,Dinoop Ravindran Menon,Douglas G. Osborne,Charles Preston Neff,Nicholas E. Powers,Fabia Gamboni,Adolfo G Mauro,Angelo D'Alessandro,Davide Stefanoni,Morkos A. Henen,Morkos A. Henen,Taylor S. Mills,Dennis M. de Graaf,Dennis M. de Graaf,Tania Azam,Beat Vögeli,Brent E. Palmer,Eric M. Pietras,James DeGregori,Aik Choon Tan,Leo A. B. Joosten,Mayumi Fujita,Charles A. Dinarello,Charles A. Dinarello,Carlo Marchetti +25 more
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In this paper, the formation of the pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression.Abstract:
Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples (n = 469) compared to normal skin (n = 324), with a highly significant correlation between NLRP3 and IL-1β (P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy.read more
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Macrophages as tools and targets in cancer therapy
TL;DR: In this paper , the authors proposed a set of macrophage-targeting strategies that include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions.
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Tumor NLRP3-Derived IL-1β Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression.
Isak W. Tengesdal,Isak W. Tengesdal,Alberto Dinarello,Alberto Dinarello,Nicholas E. Powers,Matthew A. Burchill,Leo A. B. Joosten,Carlo Marchetti,Charles A. Dinarello,Charles A. Dinarello +9 more
TL;DR: In this article, a safe-in-humans specific NLRP3 oral inhibitor was used to suppress IL-1β-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3).
Journal ArticleDOI
PMN-MDSCs accumulation induced by CXCL1 promotes CD8+ T cells exhaustion in gastric cancer.
Xingyu Zhou,Deyu Fang,Haohan Liu,Xinde Ou,Chaoyue Zhang,Zirui Zhao,Shao-Dong Zhao,Jianjun Peng,Shirong Cai,Yulong He,Jianbo Xu +10 more
TL;DR: In this paper , the authors investigated the role of myeloid-derived suppressor cells (MDSCs) in ICIs resistance of gastric cancer (GC) patients.
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Context-dependent functions of pattern recognition receptors in cancer
Si Ming Man,Brendan J. Jenkins +1 more
TL;DR: A comprehensive overview of the fast-evolving field of PRRs in cancer is provided, and the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings is discussed.
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