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.
Proc Natl Acad Sci U S A. 2019 May 28;116(22):10674-10680. doi: 10.1073/pnas.1819889116. Epub 2019 Apr 30.
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.
癌相关成纤维细胞 (CAFs) 既能抑制也能支持 T 淋巴细胞的活性，这表明 CAFs 可能被重新编程为免疫支持状态。血管紧张素受体阻滞剂 (ARBs) 将肌成纤维 CAFs 转化为静止状态，但 ARBs 是否可以将 CAFs 重新编程以促进 T 淋巴细胞活性并增强免疫治疗尚不清楚。此外，由于血管紧张素信号在肿瘤外的重要性，ARBs 的剂量受到低血压等全身不良反应的限制。为了提高 ARBs 在癌症中的疗效和特异性，以揭示其对抗肿瘤免疫的影响，我们开发了 ARB 纳米缀合物，使其在肿瘤中优先积累并发挥作用。我们创建了一个由数百种酸降解聚合物组成的多样化文库，并将 ARB 化学连接到对肿瘤 pH 最敏感的聚合物上。这些肿瘤微环境激活的 ARBs（TMA-ARBs）在循环中保持完整且无活性，同时在肿瘤中达到高浓度，在肿瘤中它们会分解为活性 ARBs。这种肿瘤优先的活性增强了 ARBs 的 CAF 重编程作用，同时消除了降压作用。值得注意的是，TMA-ARBs 缓解了免疫抑制并改善了 T 淋巴细胞活性，使患有原发性和转移性乳腺癌的小鼠对免疫检查点抑制剂的反应显著改善。
