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Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma

High‐risk neuroblastomas harbor abundant myeloid cells that suppress antitumor immunity and support tumor growth. Macrophages lacking the inhibitory NF‐κB p50 subunit adopt a pro‐inflammatory phenotype. We now report that murine 9464D neuroblastoma cells, which express high levels of exogenous MYCN,...

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Autores principales: Cui, Cheng, Barberi, Theresa, Suresh, Rahul, Friedman, Alan D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253086/
https://www.ncbi.nlm.nih.gov/pubmed/33480449
http://dx.doi.org/10.1002/1878-0261.12904
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author Cui, Cheng
Barberi, Theresa
Suresh, Rahul
Friedman, Alan D.
author_facet Cui, Cheng
Barberi, Theresa
Suresh, Rahul
Friedman, Alan D.
author_sort Cui, Cheng
collection PubMed
description High‐risk neuroblastomas harbor abundant myeloid cells that suppress antitumor immunity and support tumor growth. Macrophages lacking the inhibitory NF‐κB p50 subunit adopt a pro‐inflammatory phenotype. We now report that murine 9464D neuroblastoma cells, which express high levels of exogenous MYCN, grow slower in syngeneic p50(f/f);Lys‐Cre mice that lack p50 in macrophages and neutrophils, compared with p50(f/f) littermates. Tumors in p50(f/f);Lys‐Cre mice possess increased numbers of total and activated CD4(+) and CD8(+) T cells, and depletion of both of these T‐cell populations accelerates tumor growth. Anti‐PD‐1 T‐cell checkpoint blockade, or DNA methyltransferase and histone deacetylase inhibition, further slows tumor growth. In addition, adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC), generated either from the bone marrow of p50(−/−) mice or via nucleofection of a p50 sgRNA:Cas9 complex into wild‐type hematopoietic progenitors, also slowed growth of MHC‐matched 9464D tumors but not of MHC‐mismatched Neuro2A tumors. These findings further validate the utility of targeting myeloid NF‐κB p50 as a strategy for cancer therapy and demonstrate activity of p50‐IMC generated by gene editing of syngeneic marrow cells, a cell product relevant to clinical translation.
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spelling pubmed-82530862021-07-13 Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma Cui, Cheng Barberi, Theresa Suresh, Rahul Friedman, Alan D. Mol Oncol Research Articles High‐risk neuroblastomas harbor abundant myeloid cells that suppress antitumor immunity and support tumor growth. Macrophages lacking the inhibitory NF‐κB p50 subunit adopt a pro‐inflammatory phenotype. We now report that murine 9464D neuroblastoma cells, which express high levels of exogenous MYCN, grow slower in syngeneic p50(f/f);Lys‐Cre mice that lack p50 in macrophages and neutrophils, compared with p50(f/f) littermates. Tumors in p50(f/f);Lys‐Cre mice possess increased numbers of total and activated CD4(+) and CD8(+) T cells, and depletion of both of these T‐cell populations accelerates tumor growth. Anti‐PD‐1 T‐cell checkpoint blockade, or DNA methyltransferase and histone deacetylase inhibition, further slows tumor growth. In addition, adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC), generated either from the bone marrow of p50(−/−) mice or via nucleofection of a p50 sgRNA:Cas9 complex into wild‐type hematopoietic progenitors, also slowed growth of MHC‐matched 9464D tumors but not of MHC‐mismatched Neuro2A tumors. These findings further validate the utility of targeting myeloid NF‐κB p50 as a strategy for cancer therapy and demonstrate activity of p50‐IMC generated by gene editing of syngeneic marrow cells, a cell product relevant to clinical translation. John Wiley and Sons Inc. 2021-05-02 2021-07 /pmc/articles/PMC8253086/ /pubmed/33480449 http://dx.doi.org/10.1002/1878-0261.12904 Text en © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Cui, Cheng
Barberi, Theresa
Suresh, Rahul
Friedman, Alan D.
Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma
title Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma
title_full Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma
title_fullStr Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma
title_full_unstemmed Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma
title_short Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma
title_sort adoptive transfer of immature myeloid cells lacking nf‐κb p50 (p50‐imc) impedes the growth of mhc‐matched high‐risk neuroblastoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253086/
https://www.ncbi.nlm.nih.gov/pubmed/33480449
http://dx.doi.org/10.1002/1878-0261.12904
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