Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells
Only a subset of patients with triple-negative breast cancer (TNBC) benefits from a combination of radio- (RT) and immunotherapy. Therefore, we aimed to examine the impact of radioresistance and brain metastasizing potential on the immunological phenotype of TNBC cells following hypofractionated RT...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.981239/full |
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| author | Simon Gehre Simon Gehre Simon Gehre Felix Meyer Azzaya Sengedorj Azzaya Sengedorj Azzaya Sengedorj Fridolin Grottker Fridolin Grottker Fridolin Grottker Clara M. Reichardt Clara M. Reichardt Clara M. Reichardt Jannik Alomo Jannik Alomo Jannik Alomo Kerstin Borgmann Benjamin Frey Benjamin Frey Benjamin Frey Rainer Fietkau Rainer Fietkau Michael Rückert Michael Rückert Michael Rückert Udo S. Gaipl Udo S. Gaipl Udo S. Gaipl |
| author_facet | Simon Gehre Simon Gehre Simon Gehre Felix Meyer Azzaya Sengedorj Azzaya Sengedorj Azzaya Sengedorj Fridolin Grottker Fridolin Grottker Fridolin Grottker Clara M. Reichardt Clara M. Reichardt Clara M. Reichardt Jannik Alomo Jannik Alomo Jannik Alomo Kerstin Borgmann Benjamin Frey Benjamin Frey Benjamin Frey Rainer Fietkau Rainer Fietkau Michael Rückert Michael Rückert Michael Rückert Udo S. Gaipl Udo S. Gaipl Udo S. Gaipl |
| author_sort | Simon Gehre |
| collection | DOAJ |
| description | Only a subset of patients with triple-negative breast cancer (TNBC) benefits from a combination of radio- (RT) and immunotherapy. Therefore, we aimed to examine the impact of radioresistance and brain metastasizing potential on the immunological phenotype of TNBC cells following hypofractionated RT by analyzing cell death, immune checkpoint molecule (ICM) expression and activation of human monocyte-derived dendritic cells (DCs). MDA-MB-231 triple-negative breast cancer tumor cells were used as model system. Apoptosis was the dominant cell death form of brain metastasizing tumor cells, while Hsp70 release was generally significantly increased following RT and went along with necrosis induction. The ICMs PD-L1, PD-L2, HVEM, ICOS-L, CD137-L and OX40-L were found on the tumor cell surfaces and were significantly upregulated by RT with 5 x 5.2 Gy. Strikingly, the expression of immune suppressive ICMs was significantly higher on radioresistant clones compared to their respective non-radioresistant ones. Although hypofractionated RT led to significant cell death induction and release of Hsp70 in all tumor cell lines, human monocyte-derived DCs were not activated after co-incubation with RT-treated tumor cells. We conclude that radioresistance is a potent driver of immune suppressive ICM expression on the surface of TNBC MDA-MB-231 cells. This mechanism is generally known to predominantly influence the effector phase, rather than the priming phase, of anti-tumor immune responses. |
| first_indexed | 2024-04-09T17:11:11Z |
| format | Article |
| id | doaj.art-2c3daa9acc1c4ab1be80ebca2d3caa0b |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-09T17:11:11Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-2c3daa9acc1c4ab1be80ebca2d3caa0b2023-04-20T05:55:05ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-04-011310.3389/fonc.2023.981239981239Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cellsSimon Gehre0Simon Gehre1Simon Gehre2Felix Meyer3Azzaya Sengedorj4Azzaya Sengedorj5Azzaya Sengedorj6Fridolin Grottker7Fridolin Grottker8Fridolin Grottker9Clara M. Reichardt10Clara M. Reichardt11Clara M. Reichardt12Jannik Alomo13Jannik Alomo14Jannik Alomo15Kerstin Borgmann16Benjamin Frey17Benjamin Frey18Benjamin Frey19Rainer Fietkau20Rainer Fietkau21Michael Rückert22Michael Rückert23Michael Rückert24Udo S. Gaipl25Udo S. Gaipl26Udo S. Gaipl27Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyLaboratory of Radiobiology and Experimental Radiooncology, Department of Radiotherapy and Radiation Oncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyTranslational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyTranslational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyTranslational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyTranslational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyLaboratory of Radiobiology and Experimental Radiooncology, Department of Radiotherapy and Radiation Oncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyTranslational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyTranslational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyTranslational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, GermanyOnly a subset of patients with triple-negative breast cancer (TNBC) benefits from a combination of radio- (RT) and immunotherapy. Therefore, we aimed to examine the impact of radioresistance and brain metastasizing potential on the immunological phenotype of TNBC cells following hypofractionated RT by analyzing cell death, immune checkpoint molecule (ICM) expression and activation of human monocyte-derived dendritic cells (DCs). MDA-MB-231 triple-negative breast cancer tumor cells were used as model system. Apoptosis was the dominant cell death form of brain metastasizing tumor cells, while Hsp70 release was generally significantly increased following RT and went along with necrosis induction. The ICMs PD-L1, PD-L2, HVEM, ICOS-L, CD137-L and OX40-L were found on the tumor cell surfaces and were significantly upregulated by RT with 5 x 5.2 Gy. Strikingly, the expression of immune suppressive ICMs was significantly higher on radioresistant clones compared to their respective non-radioresistant ones. Although hypofractionated RT led to significant cell death induction and release of Hsp70 in all tumor cell lines, human monocyte-derived DCs were not activated after co-incubation with RT-treated tumor cells. We conclude that radioresistance is a potent driver of immune suppressive ICM expression on the surface of TNBC MDA-MB-231 cells. This mechanism is generally known to predominantly influence the effector phase, rather than the priming phase, of anti-tumor immune responses.https://www.frontiersin.org/articles/10.3389/fonc.2023.981239/fullradiotherapybreast cancerradioresistanceimmune checkpoint moleculesdendritic cellstumor cell death |
| spellingShingle | Simon Gehre Simon Gehre Simon Gehre Felix Meyer Azzaya Sengedorj Azzaya Sengedorj Azzaya Sengedorj Fridolin Grottker Fridolin Grottker Fridolin Grottker Clara M. Reichardt Clara M. Reichardt Clara M. Reichardt Jannik Alomo Jannik Alomo Jannik Alomo Kerstin Borgmann Benjamin Frey Benjamin Frey Benjamin Frey Rainer Fietkau Rainer Fietkau Michael Rückert Michael Rückert Michael Rückert Udo S. Gaipl Udo S. Gaipl Udo S. Gaipl Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells Frontiers in Oncology radiotherapy breast cancer radioresistance immune checkpoint molecules dendritic cells tumor cell death |
| title | Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells |
| title_full | Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells |
| title_fullStr | Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells |
| title_full_unstemmed | Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells |
| title_short | Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells |
| title_sort | clonogenicity based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of mda mb 231 triple negative breast cancer cells |
| topic | radiotherapy breast cancer radioresistance immune checkpoint molecules dendritic cells tumor cell death |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.981239/full |
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