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Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy
Name
10674.full.pdf
Description
Published version
Size
848.4 KB
Format
Adobe PDF
Checksum (MD5)
40f50a7a1ba2e981432628dfb59181ee
Author(s)
Chauhan, Vikash P
Chen, Ivy X
Tong, Rong
Ng, Mei Rosa
Martin, John D
Naxerova, Kamila
Wu, Michelle W
Huang, Peigen
Boucher, Yves
Kohane, Daniel S
Date Issued
2019
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Version
Final published version
Abstract
© 2019 National Academy of Sciences. All rights reserved. Cancer-associated fibroblasts (CAFs) can either suppress or support T lymphocyte activity, suggesting that CAFs may be reprogrammable to an immunosupportive state. Angiotensin receptor blockers (ARBs) convert myofibroblast CAFs to a quiescent state, but whether ARBs can reprogram CAFs to promote T lymphocyte activity and enhance immunotherapy is unknown. Moreover, ARB doses are limited by systemic adverse effects such as hypotension due to the importance of angiotensin signaling outside tumors. To enhance the efficacy and specificity of ARBs in cancer with the goal of revealing their effects on antitumor immunity, we developed ARB nanoconjugates that preferentially accumulate and act in tumors. We created a diverse library of hundreds of aciddegradable polymers and chemically linked ARBs to the polymer most sensitive to tumor pH. These tumor microenvironmentactivated ARBs (TMA-ARBs) remain intact and inactive in circulation while achieving high concentrations in tumors, wherein they break down to active ARBs. This tumor-preferential activity enhances the CAF-reprogramming effects of ARBs while eliminating blood pressure-lowering effects. Notably, TMA-ARBs alleviate immunosuppression and improve T lymphocyte activity, enabling dramatically improved responses to immune-checkpoint blockers in mice with primary as well as metastatic breast cancer.
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
10.1073/pnas.1819889116
