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Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions
Suppressive myeloid cells, including monocyte and neutrophil populations, play a vital role in the metastatic cascade and can inhibit the anti-tumor function of cytotoxic T-cells. Cargo-free polymeric nanoparticles (NPs) have been shown to modulate innate immune cell responses in multiple pathologie...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9720131/ https://www.ncbi.nlm.nih.gov/pubmed/36479083 http://dx.doi.org/10.3389/fonc.2022.1039993 |
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author | Raghani, Ravi M. Ma, Jeffrey A. Zhang, Yining Orbach, Sophia M. Wang, Jing Zeinali, Mina Nagrath, Sunitha Kakade, Sandeep Xu, Qichen Podojil, Joseph R. Murthy, Tushar Elhofy, Adam Jeruss, Jacqueline S. Shea, Lonnie D. |
author_facet | Raghani, Ravi M. Ma, Jeffrey A. Zhang, Yining Orbach, Sophia M. Wang, Jing Zeinali, Mina Nagrath, Sunitha Kakade, Sandeep Xu, Qichen Podojil, Joseph R. Murthy, Tushar Elhofy, Adam Jeruss, Jacqueline S. Shea, Lonnie D. |
author_sort | Raghani, Ravi M. |
collection | PubMed |
description | Suppressive myeloid cells, including monocyte and neutrophil populations, play a vital role in the metastatic cascade and can inhibit the anti-tumor function of cytotoxic T-cells. Cargo-free polymeric nanoparticles (NPs) have been shown to modulate innate immune cell responses in multiple pathologies of aberrant inflammation. Here, we test the hypothesis that the intravenous administration of drug-free NPs in the 4T1 murine model of metastatic triple-negative breast cancer can reduce metastatic colonization of the lungs, the primary metastatic site, by targeting the pro-tumor immune cell mediators of metastatic progression. In vivo studies demonstrated that NP administration reprograms the immune milieu of the lungs and reduces pulmonary metastases. Single-cell RNA sequencing of the lungs revealed that intravenous NP administration alters myeloid cell phenotype and function, skewing populations toward inflammatory, anti-tumor phenotypes and away from pro-tumor phenotypes. Monocytes, neutrophils, and dendritic cells in the lungs of NP-treated mice upregulate gene pathways associated with IFN signaling, TNF signaling, and antigen presentation. In a T-cell deficient model, NP administration failed to abrogate pulmonary metastases, implicating the vital role of T-cells in the NP-mediated reduction of metastases. NPs delivered as an adjuvant therapy, following surgical resection of the primary tumor, led to clearance of established pulmonary metastases in all treated mice. Collectively, these results demonstrate that the in vivo administration of cargo-free NPs reprograms myeloid cell responses at the lungs and promotes the clearance of pulmonary metastases in a method of action dependent on functional T-cells. |
format | Online Article Text |
id | pubmed-9720131 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97201312022-12-06 Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions Raghani, Ravi M. Ma, Jeffrey A. Zhang, Yining Orbach, Sophia M. Wang, Jing Zeinali, Mina Nagrath, Sunitha Kakade, Sandeep Xu, Qichen Podojil, Joseph R. Murthy, Tushar Elhofy, Adam Jeruss, Jacqueline S. Shea, Lonnie D. Front Oncol Oncology Suppressive myeloid cells, including monocyte and neutrophil populations, play a vital role in the metastatic cascade and can inhibit the anti-tumor function of cytotoxic T-cells. Cargo-free polymeric nanoparticles (NPs) have been shown to modulate innate immune cell responses in multiple pathologies of aberrant inflammation. Here, we test the hypothesis that the intravenous administration of drug-free NPs in the 4T1 murine model of metastatic triple-negative breast cancer can reduce metastatic colonization of the lungs, the primary metastatic site, by targeting the pro-tumor immune cell mediators of metastatic progression. In vivo studies demonstrated that NP administration reprograms the immune milieu of the lungs and reduces pulmonary metastases. Single-cell RNA sequencing of the lungs revealed that intravenous NP administration alters myeloid cell phenotype and function, skewing populations toward inflammatory, anti-tumor phenotypes and away from pro-tumor phenotypes. Monocytes, neutrophils, and dendritic cells in the lungs of NP-treated mice upregulate gene pathways associated with IFN signaling, TNF signaling, and antigen presentation. In a T-cell deficient model, NP administration failed to abrogate pulmonary metastases, implicating the vital role of T-cells in the NP-mediated reduction of metastases. NPs delivered as an adjuvant therapy, following surgical resection of the primary tumor, led to clearance of established pulmonary metastases in all treated mice. Collectively, these results demonstrate that the in vivo administration of cargo-free NPs reprograms myeloid cell responses at the lungs and promotes the clearance of pulmonary metastases in a method of action dependent on functional T-cells. Frontiers Media S.A. 2022-11-21 /pmc/articles/PMC9720131/ /pubmed/36479083 http://dx.doi.org/10.3389/fonc.2022.1039993 Text en Copyright © 2022 Raghani, Ma, Zhang, Orbach, Wang, Zeinali, Nagrath, Kakade, Xu, Podojil, Murthy, Elhofy, Jeruss and Shea https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Raghani, Ravi M. Ma, Jeffrey A. Zhang, Yining Orbach, Sophia M. Wang, Jing Zeinali, Mina Nagrath, Sunitha Kakade, Sandeep Xu, Qichen Podojil, Joseph R. Murthy, Tushar Elhofy, Adam Jeruss, Jacqueline S. Shea, Lonnie D. Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions |
title | Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions |
title_full | Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions |
title_fullStr | Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions |
title_full_unstemmed | Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions |
title_short | Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions |
title_sort | myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9720131/ https://www.ncbi.nlm.nih.gov/pubmed/36479083 http://dx.doi.org/10.3389/fonc.2022.1039993 |
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