Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy
Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy
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DOI：
10.1073/pnas.1819889116
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发表时间：
2019-05-28
影响因子：
11.1
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
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作者：
Chauhan, Vikash P.;Chen, Ivy X.;Jain, Rakesh K.
癌症相关成纤维细胞（CAFs）可以抑制或支持T淋巴细胞活性，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）可将肌成纤维细胞CAFs转化为静止状态，但ARBs是否可以重编程CAFs以促进T淋巴细胞活性并增强免疫治疗尚不清楚。此外，由于肿瘤外血管紧张素信号的重要性，ARB剂量受到全身不良反应（如低血压）的限制。为了提高ARB在肿瘤中的疗效和特异性，揭示其抗肿瘤免疫的作用，我们开发了在肿瘤中优先积累和作用的ARB纳米偶联物。我们创建了一个包含数百种酸可降解聚合物的多样化文库，并将arb与对肿瘤ph最敏感的聚合物进行化学连接。这些肿瘤微环境激活的arb （tma - arb）在循环中保持完整和无活性，同时在肿瘤中达到高浓度，其中它们分解为活性arb。这种肿瘤偏好活性增强了arb的ca -重编程作用，同时消除了降血压的作用。值得注意的是，TMA-ARBs减轻了免疫抑制并提高了T淋巴细胞活性，从而显著改善了原发性和转移性乳腺癌小鼠对免疫检查点阻断剂的反应。
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.