Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1783363986232705024 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6192988 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT florescatherinet linccr2hematopoieticstemandprogenitorcellsovercomeresistancetopd1blockade AT wildestylerj linccr2hematopoieticstemandprogenitorcellsovercomeresistancetopd1blockade AT drakejeffreya linccr2hematopoieticstemandprogenitorcellsovercomeresistancetopd1blockade AT mooregingerl linccr2hematopoieticstemandprogenitorcellsovercomeresistancetopd1blockade AT deanbaylidivita linccr2hematopoieticstemandprogenitorcellsovercomeresistancetopd1blockade AT abrahamrebeccas linccr2hematopoieticstemandprogenitorcellsovercomeresistancetopd1blockade AT mitchellduanea linccr2hematopoieticstemandprogenitorcellsovercomeresistancetopd1blockade |