Dual CSF1R inhibition and CD40 activation demonstrates anti-tumor activity in a 3D macrophage- HER2+ breast cancer spheroid model
The complex interaction between tumor-associated macrophages (TAMs) and tumor cells through soluble factors provides essential cues for breast cancer progression. TAMs-targeted therapies have shown promising clinical therapeutical potential against cancer progression. The molecular mechanisms underl...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Bioengineering and Biotechnology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fbioe.2023.1159819/full |
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| author | Manuel Rodriguez-Perdigon Laetitia Haeni Barbara Rothen-Rutishauser Curzio Rüegg |
| author_facet | Manuel Rodriguez-Perdigon Laetitia Haeni Barbara Rothen-Rutishauser Curzio Rüegg |
| author_sort | Manuel Rodriguez-Perdigon |
| collection | DOAJ |
| description | The complex interaction between tumor-associated macrophages (TAMs) and tumor cells through soluble factors provides essential cues for breast cancer progression. TAMs-targeted therapies have shown promising clinical therapeutical potential against cancer progression. The molecular mechanisms underlying the response to TAMs-targeted therapies depends on complex dynamics of immune cross-talk and its understanding is still incomplete. In vitro models are helpful to decipher complex responses to combined immunotherapies. In this study, we established and characterized a 3D human macrophage-ER+ PR+ HER2+ breast cancer model, referred to as macrophage-tumor spheroid (MTS). Macrophages integrated within the MTS had a mixed M2/M1 phenotype, abrogated the anti-proliferative effect of trastuzumab on tumor cells, and responded to IFNγ with increased M1-like polarization. The targeted treatment of MTS with a combined CSF1R kinase inhibitor and an activating anti-CD40 antibody increased M2 over M1 phenotype (CD163+/CD86+ and CD206+/CD86+ ratio) in time, abrogated G2/M cell cycle phase transition of cancer cells, promoted the secretion of TNF-α and reduced cancer cell viability. In comparison, combined treatment in a 2D macrophage-cancer cell co-culture model reduced M2 over M1 phenotype and decreased cancer cell viability. Our work shows that this MTS model is responsive to TAMs-targeted therapies, and may be used to study the response of ER+ PR+ HER2+ breast cancer lines to novel TAM-targeting therapies. |
| first_indexed | 2024-03-13T07:08:19Z |
| format | Article |
| id | doaj.art-1c602fa5bc7b4291803c0ba5afcf7106 |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-03-13T07:08:19Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-1c602fa5bc7b4291803c0ba5afcf71062023-06-06T05:11:36ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852023-06-011110.3389/fbioe.2023.11598191159819Dual CSF1R inhibition and CD40 activation demonstrates anti-tumor activity in a 3D macrophage- HER2+ breast cancer spheroid modelManuel Rodriguez-Perdigon0Laetitia Haeni1Barbara Rothen-Rutishauser2Curzio Rüegg3Laboratory of Experimental and Translational Oncology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, SwitzerlandAdolphe Merkle Institute, Faculty of Science and Medicine, University of Fribourg, Fribourg, SwitzerlandAdolphe Merkle Institute, Faculty of Science and Medicine, University of Fribourg, Fribourg, SwitzerlandLaboratory of Experimental and Translational Oncology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, SwitzerlandThe complex interaction between tumor-associated macrophages (TAMs) and tumor cells through soluble factors provides essential cues for breast cancer progression. TAMs-targeted therapies have shown promising clinical therapeutical potential against cancer progression. The molecular mechanisms underlying the response to TAMs-targeted therapies depends on complex dynamics of immune cross-talk and its understanding is still incomplete. In vitro models are helpful to decipher complex responses to combined immunotherapies. In this study, we established and characterized a 3D human macrophage-ER+ PR+ HER2+ breast cancer model, referred to as macrophage-tumor spheroid (MTS). Macrophages integrated within the MTS had a mixed M2/M1 phenotype, abrogated the anti-proliferative effect of trastuzumab on tumor cells, and responded to IFNγ with increased M1-like polarization. The targeted treatment of MTS with a combined CSF1R kinase inhibitor and an activating anti-CD40 antibody increased M2 over M1 phenotype (CD163+/CD86+ and CD206+/CD86+ ratio) in time, abrogated G2/M cell cycle phase transition of cancer cells, promoted the secretion of TNF-α and reduced cancer cell viability. In comparison, combined treatment in a 2D macrophage-cancer cell co-culture model reduced M2 over M1 phenotype and decreased cancer cell viability. Our work shows that this MTS model is responsive to TAMs-targeted therapies, and may be used to study the response of ER+ PR+ HER2+ breast cancer lines to novel TAM-targeting therapies.https://www.frontiersin.org/articles/10.3389/fbioe.2023.1159819/fullbreast cancermacrophagesspheroids3D modelcancer immunotherapyCD40 |
| spellingShingle | Manuel Rodriguez-Perdigon Laetitia Haeni Barbara Rothen-Rutishauser Curzio Rüegg Dual CSF1R inhibition and CD40 activation demonstrates anti-tumor activity in a 3D macrophage- HER2+ breast cancer spheroid model Frontiers in Bioengineering and Biotechnology breast cancer macrophages spheroids 3D model cancer immunotherapy CD40 |
| title | Dual CSF1R inhibition and CD40 activation demonstrates anti-tumor activity in a 3D macrophage- HER2+ breast cancer spheroid model |
| title_full | Dual CSF1R inhibition and CD40 activation demonstrates anti-tumor activity in a 3D macrophage- HER2+ breast cancer spheroid model |
| title_fullStr | Dual CSF1R inhibition and CD40 activation demonstrates anti-tumor activity in a 3D macrophage- HER2+ breast cancer spheroid model |
| title_full_unstemmed | Dual CSF1R inhibition and CD40 activation demonstrates anti-tumor activity in a 3D macrophage- HER2+ breast cancer spheroid model |
| title_short | Dual CSF1R inhibition and CD40 activation demonstrates anti-tumor activity in a 3D macrophage- HER2+ breast cancer spheroid model |
| title_sort | dual csf1r inhibition and cd40 activation demonstrates anti tumor activity in a 3d macrophage her2 breast cancer spheroid model |
| topic | breast cancer macrophages spheroids 3D model cancer immunotherapy CD40 |
| url | https://www.frontiersin.org/articles/10.3389/fbioe.2023.1159819/full |
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