Chauhan, Chen, and Tong et al. developed an angiotensin receptor blocker (TMA-ARB) nanoparticle comprising valsartan (an ARB) conjugated with a polymer that breaks down in the slightly acidic TME. TMA-ARB reduced hypotension and increased levels of intratumoral ARB compared with free ARB, reprogrammed cancer-associated fibroblasts from immunosuppressive to immunosupportive by reducing hypoxia and TGFβ production, and increased the activation of CD8+ T cells. Combination of TMA-ARB with anti-CTLA-4 and anti-PD-1 delayed tumor growth and prolonged survival in primary and metastatic murine models of breast cancer.
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.
Author Info: (1) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Koch Institute for Integrative Cancer
Author Info: (1) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. (2) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. (3) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. Laboratory for Biomaterials and Drug Delivery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115. Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115. Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115. (4) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (5) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. (6) Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (7) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (8) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (9) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (10) Laboratory for Biomaterials and Drug Delivery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115. Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115. Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115. (11) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 ; rlanger@mit.edu jain@steele.mgh.harvard.edu. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. (12) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; rlanger@mit.edu jain@steele.mgh.harvard.edu.
