Perdurable PD-1 blockage awakes anti-tumor immunity suppressed by precise chemotherapy
Perdurable PD-1 blockage awakes anti-tumor immunity suppressed by precise chemotherapy
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DOI：
10.1016/j.jconrel.2020.10.031
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发表时间：
2021-02-20
影响因子：
10.8
通讯作者：
You, Jian
中科院分区：
文献类型：
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作者：
Jiang, Mengshi;Li, Wei;You, Jian
纳米载体作为化疗药物的给药系统已成为肿瘤治疗的研究热点。为了提高肿瘤化疗的疗效和减少重复给药引起的毒副作用，我们合成了一种氧化还原敏感的透明质酸（HA）-维生素E琥珀酸酯（TOS）纳米胶束（HA-SS-TOS，HSST），其可主动积聚至具有高表达CD 44的肿瘤部位和转移癌细胞。在肿瘤细胞中，高GSH水平下胶束可解离，引发紫杉醇（PTX）的释放。令人惊讶的是，精确的化疗反而诱导了免疫系统的抑制趋势，表现为TGF-β的显著增加，这削弱了胶束的治疗效果。此外，高水平的TGF-β可能与癌细胞的耐药性增加有关。研究表明，阻断PD-1通路可导致TGF-β表达降低，因此，进一步制备包封PD-1拮抗剂肽A12（A12@PLGA）的PLGA微球以激活宿主免疫应答。我们的数据表明，载PTX的HSST可以准确地“找到”肿瘤以及转移癌细胞，并有效地杀死其中的大多数。持久的PD-1阻断剂的加入显著提高了PTX@HSST对多种肿瘤模型的疗效，包括肺转移性肿瘤甚至多药耐药肿瘤。因此，我们的工作提出了一个最佳的化学-免疫治疗组合系统，这对未来的癌症治疗在临床上具有深远的意义。
The application of nanocarriers as drug delivery system for chemotherapeutic drugs has become a research hotspot in cancer treatment. Chemotherapy with high tumor-targeting accuracy and drug release specificity is the key to improve the efficacy of tumor chemotherapy and reduce the side effects caused by repeated doses drugs.Here, we synthesized a redox-sensitive nano-micelle formed by hyaluronic acid (HA) conjugated with D-alpha-tocopherol succinate (TOS) using a disulfide bond as the linker (HA-SS-TOS, HSST), which could actively accumulate to the tumor sites and metastasis cancer cells with high expression of CD44. The micelles could dissociate under the high GSH level in cancer cells, triggering a release of paclitaxel (PTX). Surprisingly, the precise chemotherapy instead induced a suppressive tendency of immune system, manifested by a significant increase in TGF-beta, which weakened the therapeutic effect of micelles. Moreover, the high levels of TGF-beta might be related to the increased drug-resistance of cancer cells. Research has shown that PD-1 pathway blockade can result in reduction in TGF-beta expression, thus, a PLGA microsphere encapsulating PD-1 antagonist peptides A12 (A12@PLGA) was further prepared to activate the host immune response. Our data indicated that PTX-loaded HSST could accurately "find" the tumors as well as metastasis cancer cells, and efficiently kill most of them. The joining of a durable PD-1 blockage significantly boosted the efficacy of PTX@HSST on multiple tumor models, including lung metastatic tumors and even multidrug-resistant tumors. Thus, our work presented an optimal chemo-immunotherapy combined system, which shows profound significance for future cancer therapy in clinic.