Ternary Regulation of Tumor Microenvironment by Heparanase-Sensitive Micelle-Loaded Monocytes Improves Chemo-Immunotherapy of Metastatic Breast Cancer
Ternary Regulation of Tumor Microenvironment by Heparanase-Sensitive Micelle-Loaded Monocytes Improves Chemo-Immunotherapy of Metastatic Breast Cancer
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乙酰肝素酶敏感胶束负载单核细胞对肿瘤微环境的三元调节改善了转移性乳腺癌的化学免疫治疗
DOI：
10.1002/adfm.202007402
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发表时间：
2020-12-16
影响因子：
19
通讯作者：
Yin, Qi
中科院分区：
文献类型：
--
作者：
Lang, Tianqun;Zheng, Zhong;Yin, Qi
肿瘤免疫治疗方法如程序性细胞死亡-1/程序性细胞死亡配体1（PD-1/PD-L1）检查点阻断和吲哚胺2，3-双加氧酶（IDO）抑制被证明可促进针对肿瘤的免疫应答。不幸的是，由于肿瘤微环境中复杂的免疫抑制机制，它们的阳性反应率不令人满意，这可能通过将多种免疫调节剂和化疗剂整合在一起来挽救。为了改善转移性乳腺癌的联合治疗，设计了一种三元乙酰肝素酶（Hpa）敏感的胶束负载的单核细胞递送系统，称为HDNH@MC，其利用Ly 6C（hi）单核细胞被募集到肿瘤部位的能力和Hpa在肿瘤中的过表达。化学治疗剂多西他赛和IDO抑制剂NLG 919的前药通过将它们缀合在Hpa的底物硫酸乙酰肝素上来合成。然后制备PD-1/PD-L1抑制剂HY 19991-包封的前药胶束@Ly6C（hi）单核细胞系统。HNDH@MC能提高4 T1乳腺癌小鼠模型肿瘤内药物浓度，解除免疫抑制，增强CD 8（+）T细胞的浸润和活性，具有显著的抗癌作用。肺转移受到抑制，小鼠存活时间延长。HNDH@MC是肿瘤靶向化疗和免疫治疗协同作用的一种有希望的治疗转移性乳腺癌的选择。
Tumor immunotherapy approaches such as programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) checkpoint blockade and indoleamine 2,3-dioxygenase (IDO) inhibition are proven to promote immune response against tumors. Unfortunately, their positive response rates are unsatisfactory due to complicated immunosuppressive mechanisms in the tumor microenvironment, which can probably be rescued by integrating multiple immunoregulators and chemotherapeutic agents together. To improve the combination therapy of metastatic breast cancer, a ternary heparanase (Hpa)-sensitive micelle-loaded monocyte delivery system, termed as HDNH@MC, is designed, exploiting the capacity of Ly6C(hi) monocytes to be recruited to tumor sites and the overexpression of Hpa in tumors. The prodrugs of the chemotherapeutic agent docetaxel and IDO inhibitor NLG919 are synthesized by conjugating them on the substrate of Hpa, heparan sulfate. Then the PD-1/PD-L1 inhibitor HY19991-encapsulating prodrug micelle@Ly6C(hi) monocyte system is prepared. HNDH@MC elevates drug concentrations and relieves immunosuppression in tumors of 4T1 breast carcinomas mice model, thus enhancing the infiltration and activity of CD8(+) T cells and presenting significant anti-cancer effect. The lung metastasis is suppressed and the survival of mice is prolonged. HNDH@MC will be a promising option for treating metastatic breast cancer by synergy of tumor-targeting chemotherapy and immunotherapy.