气候变化领域集成服务门户(CCPortal): Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion

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DOI	10.1073/pnas.2000915118
	Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion
	Tengesdal I.W.; Menon D.R.; Osborne D.G.; Neff C.P.; Powers N.E.; Gamboni F.; Mauro A.G.; Alessandro A.D.; Stefanoni D.; Henen M.A.; Mills T.S.; De Graaf D.M.; Azam T.; Vogeli B.; Palmer B.E.; Pietras E.M.; DeGregori J.; Tan A.-C.; Joosten L.A.B.; Fujita M.; Dinarello C.A.; Marchetti C.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	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 pro-tumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti–PD-1 therapy. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	IL-1; Immunosuppression; MDSCs; NLRP3
语种	英语
scopus关键词	adaptor protein; anakinra; apoptosis associated speck like protein; cryopyrin; dapansutrile; immune checkpoint inhibitor; inflammasome; interleukin 1; interleukin 1beta; unclassified drug; animal cell; animal experiment; animal model; animal tissue; Article; cancer growth; cancer inhibition; cancer tissue; carcinogenesis; CD8+ T lymphocyte; cell expansion; controlled study; cutaneous melanoma; cytokine production; drug efficacy; enzyme activation; fluorescence resonance energy transfer; genetic analysis; human; human cell; human tissue; immunosuppressive treatment; in vivo study; inflammation; melanoma; melanoma cell; metastatic melanoma; molecularly targeted therapy; monotherapy; mouse; myeloid-derived suppressor cell; nonhuman; priority journal; regulatory T lymphocyte; signal transduction; tumor biopsy; tumor escape; tumor immunity
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180380
作者单位	Department of Medicine, University of Colorado Denver, Aurora, CO 80045, United States; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, GA Nijmegen, 6525, Netherlands; Department of Dermatology, University of Colorado Denver, Aurora, CO 80045, United States; Virginia Commonwealth University Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23230, United States; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, United States; Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Division of Hematology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, United States; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL 33612, United States
推荐引用方式 GB/T 7714	Tengesdal I.W.,Menon D.R.,Osborne D.G.,et al. Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion[J],2021,118(10).
APA	Tengesdal I.W..,Menon D.R..,Osborne D.G..,Neff C.P..,Powers N.E..,...&Marchetti C..(2021).Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Tengesdal I.W.,et al."Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).