Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis
Abstract Nano‐immunotherapy regimens have high potential to improve patient outcomes, as already demonstrated in advanced triple negative breast cancer with nanoparticle albumin‐bound paclitaxel and the immune checkpoint blocker (ICB) atezolizumab. This regimen, however, does not lead to cures with...
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| Format: | Article |
| Language: | English |
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Wiley
2021-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202001917 |
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| author | Fotios Mpekris Myrofora Panagi Chrysovalantis Voutouri John D. Martin Rekha Samuel Shinichiro Takahashi Naoto Gotohda Toshiyuki Suzuki Panagiotis Papageorgis Philippos Demetriou Chryso Pierides Laura Koumas Paul Costeas Motohiro Kojima Genichiro Ishii Anastasia Constantinidou Kazunori Kataoka Horacio Cabral Triantafyllos Stylianopoulos |
| author_facet | Fotios Mpekris Myrofora Panagi Chrysovalantis Voutouri John D. Martin Rekha Samuel Shinichiro Takahashi Naoto Gotohda Toshiyuki Suzuki Panagiotis Papageorgis Philippos Demetriou Chryso Pierides Laura Koumas Paul Costeas Motohiro Kojima Genichiro Ishii Anastasia Constantinidou Kazunori Kataoka Horacio Cabral Triantafyllos Stylianopoulos |
| author_sort | Fotios Mpekris |
| collection | DOAJ |
| description | Abstract Nano‐immunotherapy regimens have high potential to improve patient outcomes, as already demonstrated in advanced triple negative breast cancer with nanoparticle albumin‐bound paclitaxel and the immune checkpoint blocker (ICB) atezolizumab. This regimen, however, does not lead to cures with median survival lasting less than two years. Thus, understanding the mechanisms of resistance to and development of strategies to enhance nano‐immunotherapy in breast cancer are urgently needed. Here, in human tissue it is shown that blood vessels in breast cancer lung metastases are compressed leading to hypoxia. This pathophysiology exists in murine spontaneous models of triple negative breast cancer lung metastases, along with low levels of perfusion. Because this pathophysiology is consistent with elevated levels of solid stress, the mechanotherapeutic tranilast, which decompressed lung metastasis vessels, is administered to mice bearing metastases, thereby restoring perfusion and alleviating hypoxia. As a result, the nanomedicine Doxil causes cytotoxic effects into metastases more efficiently, stimulating anti‐tumor immunity. Indeed, when combining tranilast with Doxil and ICBs, synergistic effects on efficacy, with all mice cured in one of the two ICB‐insensitive tumor models investigated is resulted. These results suggest that strategies to treat breast cancer with nano‐immunotherapy should also include a mechanotherapeutic to decompress vessels. |
| first_indexed | 2024-12-13T13:45:24Z |
| format | Article |
| id | doaj.art-fb2bc88392274fe79e391c9d340b2b18 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-13T13:45:24Z |
| publishDate | 2021-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-fb2bc88392274fe79e391c9d340b2b182022-12-21T23:43:28ZengWileyAdvanced Science2198-38442021-02-0183n/an/a10.1002/advs.202001917Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung MetastasisFotios Mpekris0Myrofora Panagi1Chrysovalantis Voutouri2John D. Martin3Rekha Samuel4Shinichiro Takahashi5Naoto Gotohda6Toshiyuki Suzuki7Panagiotis Papageorgis8Philippos Demetriou9Chryso Pierides10Laura Koumas11Paul Costeas12Motohiro Kojima13Genichiro Ishii14Anastasia Constantinidou15Kazunori Kataoka16Horacio Cabral17Triantafyllos Stylianopoulos18Cancer Biophysics Laboratory Department of Mechanical and Manufacturing Engineering University of Cyprus Nicosia 1678 CyprusCancer Biophysics Laboratory Department of Mechanical and Manufacturing Engineering University of Cyprus Nicosia 1678 CyprusCancer Biophysics Laboratory Department of Mechanical and Manufacturing Engineering University of Cyprus Nicosia 1678 CyprusDepartment of Bioengineering Graduate School of Engineering The University of Tokyo Bunkyo Tokyo 113‐8656 JapanCentre for Stem Cell Research (A unit of inStem Bengaluru) Christian Medical College Campus Bagayam Vellore 560065 IndiaDepartment of Hepatobiliary‐Pancreatic Surgery National Cancer Center Hospital East Kashiwa Chiba 277‐8577 JapanDepartment of Hepatobiliary‐Pancreatic Surgery National Cancer Center Hospital East Kashiwa Chiba 277‐8577 JapanDepartment of Hepatobiliary‐Pancreatic Surgery National Cancer Center Hospital East Kashiwa Chiba 277‐8577 JapanDepartment of Life Sciences Program in Biological Sciences European University Cyprus Nicosia 2404 CyprusThe Center for the Study of Haematological and other Malignancies Nicosia 2032 CyprusThe Center for the Study of Haematological and other Malignancies Nicosia 2032 CyprusThe Center for the Study of Haematological and other Malignancies Nicosia 2032 CyprusThe Center for the Study of Haematological and other Malignancies Nicosia 2032 CyprusExploratory Oncology Research and Clinical Trial Center National Cancer Center Kashiwa Chiba 277‐8577 JapanExploratory Oncology Research and Clinical Trial Center National Cancer Center Kashiwa Chiba 277‐8577 JapanCyprus Cancer Research Institute Nicosia 2032 CyprusInnovation Center of NanoMedicine Kawasaki Institute of Industrial Promotion Kawasaki Kanagawa 210‐0821 JapanDepartment of Bioengineering Graduate School of Engineering The University of Tokyo Bunkyo Tokyo 113‐8656 JapanCancer Biophysics Laboratory Department of Mechanical and Manufacturing Engineering University of Cyprus Nicosia 1678 CyprusAbstract Nano‐immunotherapy regimens have high potential to improve patient outcomes, as already demonstrated in advanced triple negative breast cancer with nanoparticle albumin‐bound paclitaxel and the immune checkpoint blocker (ICB) atezolizumab. This regimen, however, does not lead to cures with median survival lasting less than two years. Thus, understanding the mechanisms of resistance to and development of strategies to enhance nano‐immunotherapy in breast cancer are urgently needed. Here, in human tissue it is shown that blood vessels in breast cancer lung metastases are compressed leading to hypoxia. This pathophysiology exists in murine spontaneous models of triple negative breast cancer lung metastases, along with low levels of perfusion. Because this pathophysiology is consistent with elevated levels of solid stress, the mechanotherapeutic tranilast, which decompressed lung metastasis vessels, is administered to mice bearing metastases, thereby restoring perfusion and alleviating hypoxia. As a result, the nanomedicine Doxil causes cytotoxic effects into metastases more efficiently, stimulating anti‐tumor immunity. Indeed, when combining tranilast with Doxil and ICBs, synergistic effects on efficacy, with all mice cured in one of the two ICB‐insensitive tumor models investigated is resulted. These results suggest that strategies to treat breast cancer with nano‐immunotherapy should also include a mechanotherapeutic to decompress vessels.https://doi.org/10.1002/advs.202001917immune checkpoint inhibitionnanomedicinestroma normalizationtumor microenvironmentvascular normalization |
| spellingShingle | Fotios Mpekris Myrofora Panagi Chrysovalantis Voutouri John D. Martin Rekha Samuel Shinichiro Takahashi Naoto Gotohda Toshiyuki Suzuki Panagiotis Papageorgis Philippos Demetriou Chryso Pierides Laura Koumas Paul Costeas Motohiro Kojima Genichiro Ishii Anastasia Constantinidou Kazunori Kataoka Horacio Cabral Triantafyllos Stylianopoulos Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis Advanced Science immune checkpoint inhibition nanomedicine stroma normalization tumor microenvironment vascular normalization |
| title | Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis |
| title_full | Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis |
| title_fullStr | Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis |
| title_full_unstemmed | Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis |
| title_short | Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis |
| title_sort | normalizing the microenvironment overcomes vessel compression and resistance to nano immunotherapy in breast cancer lung metastasis |
| topic | immune checkpoint inhibition nanomedicine stroma normalization tumor microenvironment vascular normalization |
| url | https://doi.org/10.1002/advs.202001917 |
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