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.
Highlights
It is estimated that less than 15% of cancer patients benefit from Immune checkpoint blockade (ICB) monotherapies,[2] while immunotherapy has failed to lead to durable therapeutic outcomes in triple negative breast cancer
As far as Doxil treatment is concerned, we found that Doxil improves perfusion only in the 4T1 and not the E0771 metastases but the combination of tranilast-Doxil optimizes the normalization effects of tranilast, improving further extracellular matrix (ECM) reduction, perfusion and oxygenation (Figure 2; Figure S2, Supporting Information)
Using metastasis data from patients and mice, we demonstrated that vessel compression occurs in breast cancer lung metastases causing hypo-perfusion and hypoxia
Summary
Immune checkpoint blockade (ICB) has been approved as a monotherapy or in combination with other therapies for several types of solid tumors, including metastatic triple negative breast cancer.[1,2] The use of antibodies against programmed cell death protein 1 and its ligand (anti-PD-1/PD-L1) or cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) is changing the standard of care in cancer treatment and currently there are numerous ongoing clinical trials employing ICB, which are expected to extend its clinical application to more tumor types.[3,4] it is estimated that less than 15% of cancer patients benefit from ICB monotherapies,[2] while immunotherapy has failed to lead to durable therapeutic outcomes in triple negative breast cancer. K. Kataoka Institute for Future Initiatives The University of Tokyo Bunkyo, Tokyo 113-0033, Japan shown that the antihistamine and anti-fibrotic drug tranilast, a known TGF-β inhibitor, combined with the approved pegylated liposomal doxorubicin, Doxil, can optimize normalization of the primary breast tumor micro-environment, improving perfusion. Tranilast-Doxil combination further improves perfusion and increases immunogenic cell death in lung metastases, enhances the immune metastatic microenvironment and improves the efficacy of ICBs in metastatic 4T1 and E0771 triple negative breast cancer models. All mice bearing E0771 tumors that received combined treatment with tranilast and nano-immunotherapy (Doxil + ICB) survived and were cured as indicated by the failure of tumor growth after cancer cell re-implantation and the complete lack of lung metastatic lesions
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