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Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers

Tumor-associated inflammation leads to dysregulated cytokine production that promotes tumor immune evasion and anti-tumor immunity dysfunction. In advanced stage breast cancer, the proinflammatory cytokine IL-1β is overexpressed due to large proportions of activated myeloid cells in the tumor microe...

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Autores principales: Tengesdal, Isak W., Li, Suzhao, Powers, Nicholas E., May, Makenna, Neff, Charles P., Joosten, Leo A. B., Marchetti, Carlo, Dinarello, Charles A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144656/
https://www.ncbi.nlm.nih.gov/pubmed/35631400
http://dx.doi.org/10.3390/ph15050574
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author Tengesdal, Isak W.
Li, Suzhao
Powers, Nicholas E.
May, Makenna
Neff, Charles P.
Joosten, Leo A. B.
Marchetti, Carlo
Dinarello, Charles A.
author_facet Tengesdal, Isak W.
Li, Suzhao
Powers, Nicholas E.
May, Makenna
Neff, Charles P.
Joosten, Leo A. B.
Marchetti, Carlo
Dinarello, Charles A.
author_sort Tengesdal, Isak W.
collection PubMed
description Tumor-associated inflammation leads to dysregulated cytokine production that promotes tumor immune evasion and anti-tumor immunity dysfunction. In advanced stage breast cancer, the proinflammatory cytokine IL-1β is overexpressed due to large proportions of activated myeloid cells in the tumor microenvironment (TME). Here, we demonstrate the role of the host nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing 3 (NLRP3) inflammasome in metastatic breast cancer. In vitro, we show that stimulation of THP-1 cells with conditioned media collected from MDA-MB-468 cells induced NLRP3 activation and increased Pdcd1l1 expression. In vivo, mice deficient in NLRP3 orthotopically implanted with metastatic breast cancer cell line (E0771) showed significant reduction in tumor growth (p < 0.05) and increased survival (p < 0.01). Inhibition of NLRP3 with the small molecule OLT1177(®) reduced expression of Pdcd1l1 (p < 0.001), Casp1 (p < 0.01) and Il1b (p < 0.01) in primary tumors. Furthermore, tumor-bearing mice receiving OLT1177(®) showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) (p < 0.001) and increased CD8(+) T cells (p < 0.05) and NK cells (p < 0.05) in the TME. NLRP3 inhibition in addition to anti-PD-1 treatment significantly reduced tumor growth from the monotherapies (p < 0.05). These data define NLRP3 activation as a key driver of immune suppression in metastatic breast cancers. Furthermore, this study suggests NLRP3 as a valid target to increase efficacy of immunotherapy with checkpoint inhibitor in metastatic breast cancers.
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spelling pubmed-91446562022-05-29 Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers Tengesdal, Isak W. Li, Suzhao Powers, Nicholas E. May, Makenna Neff, Charles P. Joosten, Leo A. B. Marchetti, Carlo Dinarello, Charles A. Pharmaceuticals (Basel) Article Tumor-associated inflammation leads to dysregulated cytokine production that promotes tumor immune evasion and anti-tumor immunity dysfunction. In advanced stage breast cancer, the proinflammatory cytokine IL-1β is overexpressed due to large proportions of activated myeloid cells in the tumor microenvironment (TME). Here, we demonstrate the role of the host nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing 3 (NLRP3) inflammasome in metastatic breast cancer. In vitro, we show that stimulation of THP-1 cells with conditioned media collected from MDA-MB-468 cells induced NLRP3 activation and increased Pdcd1l1 expression. In vivo, mice deficient in NLRP3 orthotopically implanted with metastatic breast cancer cell line (E0771) showed significant reduction in tumor growth (p < 0.05) and increased survival (p < 0.01). Inhibition of NLRP3 with the small molecule OLT1177(®) reduced expression of Pdcd1l1 (p < 0.001), Casp1 (p < 0.01) and Il1b (p < 0.01) in primary tumors. Furthermore, tumor-bearing mice receiving OLT1177(®) showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) (p < 0.001) and increased CD8(+) T cells (p < 0.05) and NK cells (p < 0.05) in the TME. NLRP3 inhibition in addition to anti-PD-1 treatment significantly reduced tumor growth from the monotherapies (p < 0.05). These data define NLRP3 activation as a key driver of immune suppression in metastatic breast cancers. Furthermore, this study suggests NLRP3 as a valid target to increase efficacy of immunotherapy with checkpoint inhibitor in metastatic breast cancers. MDPI 2022-05-04 /pmc/articles/PMC9144656/ /pubmed/35631400 http://dx.doi.org/10.3390/ph15050574 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tengesdal, Isak W.
Li, Suzhao
Powers, Nicholas E.
May, Makenna
Neff, Charles P.
Joosten, Leo A. B.
Marchetti, Carlo
Dinarello, Charles A.
Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers
title Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers
title_full Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers
title_fullStr Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers
title_full_unstemmed Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers
title_short Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers
title_sort activation of host-nlrp3 inflammasome in myeloid cells dictates response to anti-pd-1 therapy in metastatic breast cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144656/
https://www.ncbi.nlm.nih.gov/pubmed/35631400
http://dx.doi.org/10.3390/ph15050574
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