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Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer.

Publication ,  Journal Article
Biswas, S; Mandal, G; Roy Chowdhury, S; Purohit, S; Payne, KK; Anadon, C; Gupta, A; Swanson, P; Yu, X; Conejo-Garcia, JR; Bhattacharyya, A
Published in: J Immunol
December 15, 2019

Tumor-associated macrophages are major contributors to malignant progression and resistance to immunotherapy, but the mechanisms governing their differentiation from immature myeloid precursors remain incompletely understood. In this study, we demonstrate that exosomes secreted by human and mouse tumor-educated mesenchymal stem cells (MSCs) drive accelerated breast cancer progression by inducing differentiation of monocytic myeloid-derived suppressor cells into highly immunosuppressive M2-polarized macrophages at tumor beds. Mechanistically, MSC-derived exosomes but not exosomes from tumor cells contain TGF-β, C1q, and semaphorins, which promote myeloid tolerogenic activity by driving PD-L1 overexpression in both immature myelomonocytic precursors and committed CD206+ macrophages and by inducing differentiation of MHC class II+ macrophages with enhanced l-Arginase activity and IL-10 secretion at tumor beds. Accordingly, administration of tumor-associated murine MSC-derived exosomes accelerates tumor growth by dampening antitumor immunity, and macrophage depletion eliminates exosome-dependent differences in malignant progression. Our results unveil a new role for MSC-derived exosomes in the differentiation of myeloid-derived suppressor cells into macrophages, which governs malignant growth.

Duke Scholars

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

December 15, 2019

Volume

203

Issue

12

Start / End Page

3447 / 3460

Location

United States

Related Subject Headings

  • Myeloid Cells
  • Mice
  • Mesenchymal Stem Cells
  • Macrophages
  • Macrophage Activation
  • Immunophenotyping
  • Immunomodulation
  • Immunology
  • Humans
  • Heterografts
 

Citation

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Biswas, S., Mandal, G., Roy Chowdhury, S., Purohit, S., Payne, K. K., Anadon, C., … Bhattacharyya, A. (2019). Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer. J Immunol, 203(12), 3447–3460. https://doi.org/10.4049/jimmunol.1900692
Biswas, Subir, Gunjan Mandal, Sougata Roy Chowdhury, Suman Purohit, Kyle K. Payne, Carmen Anadon, Arnab Gupta, et al. “Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer.J Immunol 203, no. 12 (December 15, 2019): 3447–60. https://doi.org/10.4049/jimmunol.1900692.
Biswas S, Mandal G, Roy Chowdhury S, Purohit S, Payne KK, Anadon C, et al. Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer. J Immunol. 2019 Dec 15;203(12):3447–60.
Biswas, Subir, et al. “Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer.J Immunol, vol. 203, no. 12, Dec. 2019, pp. 3447–60. Pubmed, doi:10.4049/jimmunol.1900692.
Biswas S, Mandal G, Roy Chowdhury S, Purohit S, Payne KK, Anadon C, Gupta A, Swanson P, Yu X, Conejo-Garcia JR, Bhattacharyya A. Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer. J Immunol. 2019 Dec 15;203(12):3447–3460.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

December 15, 2019

Volume

203

Issue

12

Start / End Page

3447 / 3460

Location

United States

Related Subject Headings

  • Myeloid Cells
  • Mice
  • Mesenchymal Stem Cells
  • Macrophages
  • Macrophage Activation
  • Immunophenotyping
  • Immunomodulation
  • Immunology
  • Humans
  • Heterografts