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CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy
The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). H...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873057/ https://www.ncbi.nlm.nih.gov/pubmed/33563975 http://dx.doi.org/10.1038/s41467-021-20893-2 |
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author | Rodriguez-Garcia, Alba Lynn, Rachel C. Poussin, Mathilde Eiva, Monika A. Shaw, Lauren C. O’Connor, Roddy S. Minutolo, Nicholas G. Casado-Medrano, Victoria Lopez, Gonzalo Matsuyama, Takami Powell, Daniel J. |
author_facet | Rodriguez-Garcia, Alba Lynn, Rachel C. Poussin, Mathilde Eiva, Monika A. Shaw, Lauren C. O’Connor, Roddy S. Minutolo, Nicholas G. Casado-Medrano, Victoria Lopez, Gonzalo Matsuyama, Takami Powell, Daniel J. |
author_sort | Rodriguez-Garcia, Alba |
collection | PubMed |
description | The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Here, we demonstrate that a subset of TAMs that express folate receptor β (FRβ) possess an immunosuppressive M2-like profile. In syngeneic tumor mouse models, chimeric antigen receptor (CAR)-T cell-mediated selective elimination of FRβ(+) TAMs in the TME results in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8(+) T cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR-T cells also improves the effectiveness of tumor-directed anti-mesothelin CAR-T cells, while simultaneous co-administration of both CAR products does not. These results highlight the pro-tumor role of FRβ(+) TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens. |
format | Online Article Text |
id | pubmed-7873057 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78730572021-02-16 CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy Rodriguez-Garcia, Alba Lynn, Rachel C. Poussin, Mathilde Eiva, Monika A. Shaw, Lauren C. O’Connor, Roddy S. Minutolo, Nicholas G. Casado-Medrano, Victoria Lopez, Gonzalo Matsuyama, Takami Powell, Daniel J. Nat Commun Article The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Here, we demonstrate that a subset of TAMs that express folate receptor β (FRβ) possess an immunosuppressive M2-like profile. In syngeneic tumor mouse models, chimeric antigen receptor (CAR)-T cell-mediated selective elimination of FRβ(+) TAMs in the TME results in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8(+) T cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR-T cells also improves the effectiveness of tumor-directed anti-mesothelin CAR-T cells, while simultaneous co-administration of both CAR products does not. These results highlight the pro-tumor role of FRβ(+) TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens. Nature Publishing Group UK 2021-02-09 /pmc/articles/PMC7873057/ /pubmed/33563975 http://dx.doi.org/10.1038/s41467-021-20893-2 Text en © The Author(s) 2021 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 Rodriguez-Garcia, Alba Lynn, Rachel C. Poussin, Mathilde Eiva, Monika A. Shaw, Lauren C. O’Connor, Roddy S. Minutolo, Nicholas G. Casado-Medrano, Victoria Lopez, Gonzalo Matsuyama, Takami Powell, Daniel J. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy |
title | CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy |
title_full | CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy |
title_fullStr | CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy |
title_full_unstemmed | CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy |
title_short | CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy |
title_sort | car-t cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873057/ https://www.ncbi.nlm.nih.gov/pubmed/33563975 http://dx.doi.org/10.1038/s41467-021-20893-2 |
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