Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy
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Fereydouni, Mohammad, et al. Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy. 2022. https://doi.org/10.17615/3s97-0p19APA
Fereydouni, M., Ahani, E., Desai, P., Motaghed, M., Dellinger, A., Metcalfe, D., Yin, Y., Lee, S., Kafri, T., Bhatt, A., Dellinger, K., & Kepley, C. (2022). Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy. https://doi.org/10.17615/3s97-0p19Chicago
Fereydouni, Mohammad, Elnaz Ahani, Parth Desai, Mona Motaghed, Anthony Dellinger, Dean D Metcalfe, Yuzhi Yin et al. 2022. Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy. https://doi.org/10.17615/3s97-0p19- Creator
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Fereydouni, Mohammad
- Other Affiliation: University of North Carolina at Greensboro
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Ahani, Elnaz
- Other Affiliation: North Carolina Agricultural and Technical State University
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Desai, Parth
- Other Affiliation: University of North Carolina at Greensboro
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Motaghed, Mona
- Other Affiliation: North Carolina Agricultural and Technical State University
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Dellinger, Anthony
- Other Affiliation: University of North Carolina at Greensboro
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Metcalfe, Dean D.
- Other Affiliation: National Institutes of Health
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Yin, Yuzhi
- Other Affiliation: National Institutes of Health
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Lee, Sung Hyun
- Affiliation: School of Medicine, Department of Microbiology and Immunology
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Kafri, Tal
- Affiliation: School of Medicine, Department of Microbiology and Immunology
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Bhatt, Aadra P.
- Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
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Dellinger, Kristen
- Other Affiliation: North Carolina Agricultural and Technical State University
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Kepley, Christopher L.
- Other Affiliation: Liberty University College of Osteopathic Medicine
- Abstract
- The diversity of autologous cells being used and investigated for cancer therapy continues to increase. Mast cells (MCs) are tissue cells that contain a unique set of anti-cancer mediators and are found in and around tumors. We sought to exploit the anti-tumor mediators in MC granules to selectively target them to tumor cells using tumor specific immunoglobin E (IgE) and controllably trigger release of anti-tumor mediators upon tumor cell engagement. We used a human HER2/neu-specific IgE to arm human MCs through the high affinity IgE receptor (FcεRI). The ability of MCs to bind to and induce apoptosis of HER2/neu-positive cancer cells in vitro and in vivo was assessed. The interactions between MCs and cancer cells were investigated in real time using confocal microscopy. The mechanism of action using cytotoxic MCs was examined using gene array profiling. Genetically manipulating autologous MC to assess the effects of MC-specific mediators have on apoptosis of tumor cells was developed using siRNA. We found that HER2/neu tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/neu-positive tumor masses in vitro. Tunneling nanotubes formed between MCs and tumor cells are described that parallel tumor cell apoptosis. In solid tumor, human breast cancer (BC) xenograft mouse models, infusion of HER2/neu IgE-sensitized human MCs co-localized to BC cells, decreased tumor burden, and prolonged overall survival without indications of toxicity. Gene microarray of tumor cells suggests a dependence on TNF and TGFβ signaling pathways leading to apoptosis. Knocking down MC-released tryptase did not affect apoptosis of cancer cells. These studies suggest MCs can be polarized from Type I hypersensitivity-mediating cells to cytotoxic cells that selectively target tumor cells and specifically triggered to release anti-tumor mediators. A strategy to investigate which MC mediators are responsible for the observed tumor killing is described so that rational decisions can be made in the future when selecting which mediators to target for deletion or those that could further polarize them to cytotoxic MC by adding other known anti-tumor agents. Using autologous human MC may provide further options for cancer therapeutics that offers a unique anti-cancer mechanism of action using tumor targeted IgE’s.
- Date of publication
- 2022
- Keyword
- DOI
- Identifier
- Resource type
- Article
- Rights statement
- In Copyright
- License
- Attribution 4.0 International
- Journal title
- Frontiers in Oncology
- Journal volume
- 12
- Language
- English
- Version
- Publisher
- ISSN
- 2234-943X
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