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Lin(−)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade

Immune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineag...

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Autores principales: Flores, Catherine T., Wildes, Tyler J., Drake, Jeffrey A., Moore, Ginger L., Dean, Bayli DiVita, Abraham, Rebecca S., Mitchell, Duane A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192988/
https://www.ncbi.nlm.nih.gov/pubmed/30333482
http://dx.doi.org/10.1038/s41467-018-06182-5
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author Flores, Catherine T.
Wildes, Tyler J.
Drake, Jeffrey A.
Moore, Ginger L.
Dean, Bayli DiVita
Abraham, Rebecca S.
Mitchell, Duane A.
author_facet Flores, Catherine T.
Wildes, Tyler J.
Drake, Jeffrey A.
Moore, Ginger L.
Dean, Bayli DiVita
Abraham, Rebecca S.
Mitchell, Duane A.
author_sort Flores, Catherine T.
collection PubMed
description Immune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineage-negative hematopoietic stem and progenitor cells (HSCs) that express C–C chemokine receptor type 2 (CCR2(+)) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC transfer with PD-1 blockade increases T-cell frequency and activation within tumors in preclinical models of glioblastoma and medulloblastoma. CCR2(+)HSCs preferentially migrate to intracranial brain tumors and differentiate into antigen-presenting cells within the tumor microenvironment and cross-present tumor-derived antigens to CD8(+) T cells. HSC transfer also rescues tumor resistance to adoptive cellular therapy in medulloblastoma and glioblastoma. Our studies demonstrate a novel role for CCR2(+)HSCs in overcoming brain tumor resistance to PD-1 checkpoint blockade and adoptive cellular therapy in multiple invasive brain tumor models.
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spelling pubmed-61929882018-10-19 Lin(−)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade Flores, Catherine T. Wildes, Tyler J. Drake, Jeffrey A. Moore, Ginger L. Dean, Bayli DiVita Abraham, Rebecca S. Mitchell, Duane A. Nat Commun Article Immune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineage-negative hematopoietic stem and progenitor cells (HSCs) that express C–C chemokine receptor type 2 (CCR2(+)) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC transfer with PD-1 blockade increases T-cell frequency and activation within tumors in preclinical models of glioblastoma and medulloblastoma. CCR2(+)HSCs preferentially migrate to intracranial brain tumors and differentiate into antigen-presenting cells within the tumor microenvironment and cross-present tumor-derived antigens to CD8(+) T cells. HSC transfer also rescues tumor resistance to adoptive cellular therapy in medulloblastoma and glioblastoma. Our studies demonstrate a novel role for CCR2(+)HSCs in overcoming brain tumor resistance to PD-1 checkpoint blockade and adoptive cellular therapy in multiple invasive brain tumor models. Nature Publishing Group UK 2018-10-17 /pmc/articles/PMC6192988/ /pubmed/30333482 http://dx.doi.org/10.1038/s41467-018-06182-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Flores, Catherine T.
Wildes, Tyler J.
Drake, Jeffrey A.
Moore, Ginger L.
Dean, Bayli DiVita
Abraham, Rebecca S.
Mitchell, Duane A.
Lin(−)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
title Lin(−)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
title_full Lin(−)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
title_fullStr Lin(−)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
title_full_unstemmed Lin(−)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
title_short Lin(−)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
title_sort lin(−)ccr2(+) hematopoietic stem and progenitor cells overcome resistance to pd-1 blockade
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192988/
https://www.ncbi.nlm.nih.gov/pubmed/30333482
http://dx.doi.org/10.1038/s41467-018-06182-5
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