Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis

• Published in: Advanced science Vol. 8; no. 3; pp. 2001917 - n/a
• Main Authors: Mpekris, Fotios, Panagi, Myrofora, Voutouri, Chrysovalantis, Martin, John D., Samuel, Rekha, Takahashi, Shinichiro, Gotohda, Naoto, Suzuki, Toshiyuki, Papageorgis, Panagiotis, Demetriou, Philippos, Pierides, Chryso, Koumas, Laura, Costeas, Paul, Kojima, Motohiro, Ishii, Genichiro, Constantinidou, Anastasia, Kataoka, Kazunori, Cabral, Horacio, Stylianopoulos, Triantafyllos
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01-02-2021; John Wiley and Sons Inc; Wiley
• Subjects: Apoptosis; Breast cancer; Cancer therapies; Collagen; Cytotoxicity; Fibroblasts; Hyaluronic acid; Hypoxia; immune checkpoint inhibition; Immunotherapy; Lectins; Metastasis; Monoclonal antibodies; nanomedicine; stroma normalization; Targeted cancer therapy; tumor microenvironment; Tumors; vascular normalization; vascular normalization; nanomedicine; stroma normalization; immune checkpoint inhibition; tumor microenvironment
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202001917

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.