Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis
| Autor: | Chryso Pierides, Shinichiro Takahashi, Naoto Gotohda, Fotios Mpekris, Chrysovalantis Voutouri, Kazunori Kataoka, Rekha Samuel, Motohiro Kojima, Laura Koumas, Paul Costeas, Toshiyuki Suzuki, Anastasia Constantinidou, John D. Martin, Myrofora Panagi, Philippos Demetriou, Genichiro Ishii, Triantafyllos Stylianopoulos, Panagiotis Papageorgis, Horacio Cabral |
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| Rok vydání: | 2021 |
| Předmět: |
General Chemical Engineering
medicine.medical_treatment Tranilast General Physics and Astronomy Medicine (miscellaneous) 02 engineering and technology 010402 general chemistry 01 natural sciences Biochemistry Genetics and Molecular Biology (miscellaneous) chemistry.chemical_compound Breast cancer Atezolizumab Medicine tumor microenvironment General Materials Science stroma normalization lcsh:Science Triple-negative breast cancer vascular normalization Tumor microenvironment Full Paper business.industry General Engineering Immunotherapy Full Papers 021001 nanoscience & nanotechnology medicine.disease nanomedicine Immune checkpoint 3. Good health 0104 chemical sciences Paclitaxel chemistry Cancer research immune checkpoint inhibition lcsh:Q 0210 nano-technology business medicine.drug |
| Zdroj: | Advanced Science Advanced Science, Vol 8, Iss 3, Pp n/a-n/a (2021) |
| ISSN: | 2198-3844 |
| DOI: | 10.1002/advs.202001917 |
| Popis: | 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. Combinatorial treatment of a mechanotherapeutic and nanomedicine normalizes metastasis microenvironment by decreasing fibrosis and hypoxia and skewing TAMs polarization from immunosuppressive M2‐like TAMs to immunostimulatory M1‐like TAMs. Improved perfusion and oxygenation leads to improved efficacy of immune checkpoint blockers and cure. |
| Databáze: | OpenAIRE |
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