Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer
DNA damage repair and tumor hypoxia contribute to intratumoral cellular and molecular heterogeneity and affect radiation response. The goal of this study is to investigate anti-HER2-induced radiosensitization of the tumor microenvironment to enhance fractionated radiotherapy in models of HER2+ breas...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/4/1015 |
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| author | Patrick N. Song Ameer Mansur Yun Lu Deborah Della Manna Andrew Burns Sharon Samuel Katherine Heinzman Suzanne E. Lapi Eddy S. Yang Anna G. Sorace |
| author_facet | Patrick N. Song Ameer Mansur Yun Lu Deborah Della Manna Andrew Burns Sharon Samuel Katherine Heinzman Suzanne E. Lapi Eddy S. Yang Anna G. Sorace |
| author_sort | Patrick N. Song |
| collection | DOAJ |
| description | DNA damage repair and tumor hypoxia contribute to intratumoral cellular and molecular heterogeneity and affect radiation response. The goal of this study is to investigate anti-HER2-induced radiosensitization of the tumor microenvironment to enhance fractionated radiotherapy in models of HER2+ breast cancer. This is monitored through in vitro and in vivo studies of phosphorylated γ-H2AX, [<sup>18</sup>F]-fluoromisonidazole (FMISO)-PET, and transcriptomic analysis. In vitro, HER2+ breast cancer cell lines were treated with trastuzumab prior to radiation and DNA double-strand breaks (DSB) were quantified. In vivo, HER2+ human cell line or patient-derived xenograft models were treated with trastuzumab, fractionated radiation, or a combination and monitored longitudinally with [<sup>18</sup>F]-FMISO-PET. In vitro DSB analysis revealed that trastuzumab administered prior to fractionated radiation increased DSB. In vivo, trastuzumab prior to fractionated radiation significantly reduced hypoxia, as detected through decreased [<sup>18</sup>F]-FMISO SUV, synergistically improving long-term tumor response. Significant changes in IL-2, IFN-gamma, and THBS-4 were observed in combination-treated tumors. Trastuzumab prior to fractionated radiation synergistically increases radiotherapy in vitro and in vivo in HER2+ breast cancer which is independent of anti-HER2 response alone. Modulation of the tumor microenvironment, through increased tumor oxygenation and decreased DNA damage response, can be translated to other cancers with first-line radiation therapy. |
| first_indexed | 2024-03-09T22:23:03Z |
| format | Article |
| id | doaj.art-5008f5f7e201442083385f6eecf69154 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T22:23:03Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5008f5f7e201442083385f6eecf691542023-11-23T19:10:05ZengMDPI AGCancers2072-66942022-02-01144101510.3390/cancers14041015Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast CancerPatrick N. Song0Ameer Mansur1Yun Lu2Deborah Della Manna3Andrew Burns4Sharon Samuel5Katherine Heinzman6Suzanne E. Lapi7Eddy S. Yang8Anna G. Sorace9Department of Radiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Radiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Radiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Radiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Radiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USADNA damage repair and tumor hypoxia contribute to intratumoral cellular and molecular heterogeneity and affect radiation response. The goal of this study is to investigate anti-HER2-induced radiosensitization of the tumor microenvironment to enhance fractionated radiotherapy in models of HER2+ breast cancer. This is monitored through in vitro and in vivo studies of phosphorylated γ-H2AX, [<sup>18</sup>F]-fluoromisonidazole (FMISO)-PET, and transcriptomic analysis. In vitro, HER2+ breast cancer cell lines were treated with trastuzumab prior to radiation and DNA double-strand breaks (DSB) were quantified. In vivo, HER2+ human cell line or patient-derived xenograft models were treated with trastuzumab, fractionated radiation, or a combination and monitored longitudinally with [<sup>18</sup>F]-FMISO-PET. In vitro DSB analysis revealed that trastuzumab administered prior to fractionated radiation increased DSB. In vivo, trastuzumab prior to fractionated radiation significantly reduced hypoxia, as detected through decreased [<sup>18</sup>F]-FMISO SUV, synergistically improving long-term tumor response. Significant changes in IL-2, IFN-gamma, and THBS-4 were observed in combination-treated tumors. Trastuzumab prior to fractionated radiation synergistically increases radiotherapy in vitro and in vivo in HER2+ breast cancer which is independent of anti-HER2 response alone. Modulation of the tumor microenvironment, through increased tumor oxygenation and decreased DNA damage response, can be translated to other cancers with first-line radiation therapy.https://www.mdpi.com/2072-6694/14/4/1015PDXBT474MDA-MB-361BCM 3472trastuzumab[<sup>18</sup>F]-FMISO |
| spellingShingle | Patrick N. Song Ameer Mansur Yun Lu Deborah Della Manna Andrew Burns Sharon Samuel Katherine Heinzman Suzanne E. Lapi Eddy S. Yang Anna G. Sorace Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer Cancers PDX BT474 MDA-MB-361 BCM 3472 trastuzumab [<sup>18</sup>F]-FMISO |
| title | Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer |
| title_full | Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer |
| title_fullStr | Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer |
| title_full_unstemmed | Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer |
| title_short | Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer |
| title_sort | modulation of the tumor microenvironment with trastuzumab enables radiosensitization in her2 breast cancer |
| topic | PDX BT474 MDA-MB-361 BCM 3472 trastuzumab [<sup>18</sup>F]-FMISO |
| url | https://www.mdpi.com/2072-6694/14/4/1015 |
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