TY - JOUR
T1 - Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions
AU - Raghani, Ravi M.
AU - Ma, Jeffrey A.
AU - Zhang, Yining
AU - Orbach, Sophia M.
AU - Wang, Jing
AU - Zeinali, Mina
AU - Nagrath, Sunitha
AU - Kakade, Sandeep
AU - Xu, Qichen
AU - Podojil, Joseph R.
AU - Murthy, Tushar
AU - Elhofy, Adam
AU - Jeruss, Jacqueline S.
AU - Shea, Lonnie D.
N1 - Funding Information:
Funding for this research was provided by COUR Pharmaceutical Development Co, Inc., and the National Institutes of Health under award numbers 1R01AI148076, 1R01AI155678, 1R01CA243916, and R01CA214384. Transcriptomic analyses were supported by the National Cancer Institutes of Health under Award Number P30CA046592 by use of the following Cancer Center Shared Resource: Single Cell and Spatial Analysis Shared Resource.
Funding Information:
These studies were funded, in part, by COUR Pharmaceutical Development Co, Inc., which holds the intellectual property for nanoparticles studied in this manuscript.
Publisher Copyright:
Copyright © 2022 Raghani, Ma, Zhang, Orbach, Wang, Zeinali, Nagrath, Kakade, Xu, Podojil, Murthy, Elhofy, Jeruss and Shea.
PY - 2022/11/21
Y1 - 2022/11/21
N2 - 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.
AB - 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.
KW - cancer immunotherapy
KW - immune cell reprogramming
KW - metastasis
KW - polymeric nanoparticles
KW - triple negative breast cancer
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U2 - 10.3389/fonc.2022.1039993
DO - 10.3389/fonc.2022.1039993
M3 - Article
C2 - 36479083
AN - SCOPUS:85143796872
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1039993
ER -