Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy
| Autor: | Rakesh K. Jain, Yves Boucher, Peigen Huang, Michelle W. Wu, Ivy X. Chen, Kamila Naxerova, Vikash P. Chauhan, Daniel S. Kohane, Rong Tong, Mei Rosa Ng, Robert Langer, John D. Martin |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Polymers medicine.medical_treatment urologic and male genital diseases Angiotensin Receptor Antagonists Mice Drug Delivery Systems Cancer immunotherapy Cell Line Tumor Neoplasms Renin–angiotensin system medicine Tumor Microenvironment Animals cardiovascular diseases Tumor microenvironment Multidisciplinary business.industry Cancer T lymphocyte Immunotherapy Hydrogen-Ion Concentration medicine.disease Metastatic breast cancer female genital diseases and pregnancy complications PNAS Plus Cancer research Female business Myofibroblast hormones hormone substitutes and hormone antagonists |
| Popis: | 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 acid-degradable polymers and chemically linked ARBs to the polymer most sensitive to tumor pH. These tumor microenvironment-activated 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. |
| Databáze: | OpenAIRE |
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