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 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.

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

“…Furthermore, the compression of intratumoral vessels owing to tumor stiffening and solid stress elevation can cause an inefficient and heterogeneous distribution of blood flow in the tumor resulting in insufficient and non-uniform delivery of drugs and immune cells to the tumor and hypoxia, which can further support tumor progression and metastasis [ 148 ]. Importantly, increased ECM density and vessel compression have been recently observed not only in the primary tumors but also in breast cancer metastasis in the lungs and has been related to compromised therapeutic efficacy in lung metastatic lesions [ 149 ]. Therefore, the stroma normalization strategy aims to restore vessel functionality by alleviating intratumoral solid stresses and reducing tumor stiffness [ 146 , 147 ], which allows for increased tumor perfusion and suppresses invasion and metastasis [ 150 , 151 ].…”

“…Safety concerns have been raised, though, regarding the use of antihypertensive agents in cancer patients experiencing normal blood pressure or hypotension. Hence, additional approved agents have been repurposed for priming the TME including antihistamine drugs (e.g., tranilast) [ 149 , 174 , 175 ], corticosteroids (e.g., dexamethasone) [ 176 ], anti-inflammatory (e.g., pirfenidone) [ 177 ], anti-diabetic drugs (e.g., metformin) [ 178 ], and other agents possessing anti-fibrotic effects (e.g., pentoxifylline) [ 179 ], vitamin D [ 180 ], and relaxin [ 181 , 182 , 183 , 184 ].…”

Hyperbaric Oxygen Boosts PD‐1 Antibody Delivery and T Cell Infiltration for Augmented Immune Responses Against Solid Tumors

“…[ 11 ] To this end, numerous approaches have been proposed to deplete the excessive ECM surrounding tumor nests for augmented immunotherapy. [ 7,12,13 ]…”

Endothelin Inhibition Potentiates Cancer Immunotherapy Revealing Mechanical Biomarkers Predictive of Response

“…[ 16 ] Strategies that reduce tumor stiffness to decompress vessels by reprogramming CAFs to produce and maintain less ECM potentiate ICB efficacy in ICB‐resistant mouse models of metastatic breast cancer. [ 3,17–19 ] If there was a way to decompress tumor vessels while also facilitating vessel adhesion and transmigration of T cells into the tumor parenchyma, the fraction of cancer patients that respond to ICB could increase. To this end, here we identified the nonselective endothelin receptor blocker bosentan as a “mechanotherapeutic” [ 16,20 ] capable of reducing stiffness thereby decompressing vessels and also inhibiting signaling that prevents T cells from adhering to tumor vessel walls.…”