Glycocalyx-Mimicking Nanoparticles Improve Anti-PD-L1 Cancer Immunotherapy through Reversion of Tumor-Associated Macrophages
Glycocalyx-Mimicking Nanoparticles Improve Anti-PD-L1 Cancer Immunotherapy through Reversion of Tumor-Associated Macrophages
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DOI：
10.1021/acs.biomac.8b00305
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发表时间：
2018
影响因子：
6.2
通讯作者：
Chen GS
中科院分区：
文献类型：
--
作者：
Zhang Yufei;Wu Libin;Li Zhen;Zhang Weiyi;Chen Guosong;Luo Feifei;Chu Yiwei;Chen GS
抗PD-L1单克隆抗体（αPD-L1）的免疫检查点阻断在某些癌症中取得了前所未有的临床获益，但治疗效果往往受到肿瘤相关巨噬细胞（TAM）介导的免疫抑制性肿瘤微环境的阻碍，导致对该方法的先天性耐药。为了提高检查点阻断功效，通过RAFT聚合制备两亲性二嵌段共聚物聚（吡喃甘露糖苷/吡喃半乳糖苷甲基丙烯酸酯）-嵌段-聚苯乙烯，其依次自组装成糖萼模拟纳米颗粒（GNP）以中和TAM。研究表明，GNP可以通过凝集素受体被TAM特异性内化，这导致免疫刺激性IL-12的上调和免疫抑制性IL-10、GNP酶1和CCL 22的下调，表明促肿瘤TAM向抗肿瘤表型的功能逆转。TAMs的逆转主要通过抑制STAT 6和激活NF-κB磷酸化来控制。体内治疗研究表明，GNPs通过减少肿瘤负荷显着增强αPD-L1癌症治疗的疗效。此外，GNP和αPD-L1联合治疗通过相互调节肿瘤浸润效应细胞和调节性T细胞，极大地改善了免疫抑制性肿瘤微环境。值得注意的是，我们的研究结果首次证明了含碳水化合物的合成纳米材料可以逆转TAM并改善αPD-L1癌症治疗。这项研究强调了一种有前途的策略，用于优化癌症免疫治疗中的免疫检查点阻断。
Immune checkpoint blockade by anti-PD-L1 monoclonal antibody (αPD-L1) has achieved unprecedented clinical benefits in certain cancers, whereas the therapeutic efficacy is often hindered by immunosuppressive tumor microenvironment mediated by tumor-associated macrophages (TAMs), which leads to innate resistance to this approach. To improve checkpoint blockade efficacy, the amphiphilic diblock copolymers poly(mannopyranoside/galactopyranoside methacrylate)-block-polystyrene are prepared by RAFT polymerization, which are sequentially self-assembled into glycocalyx-mimicking nanoparticles (GNPs) to neutralize TAMs. It is shown that GNPs can be specifically internalized by TAMs via lectin receptors, which results in upregulation of immunostimulatory IL-12 and downregulation of immunosuppressive IL-10, arginase 1, and CCL22, indicating functional reversion of protumor TAMs toward antitumor phenotype. The reversion of TAMs is proved to be mainly controlled by suppressing STAT6 and activating NF-κB phosphorylation. In vivo therapeutic studies have demonstrated that GNPs significantly enhance the therapeutic efficacy of αPD-L1 cancer therapy by reduction of tumor burden. Moreover, combination therapies with GNPs and αPD-L1 greatly improve immunosuppressive tumor microenvironment by reciprocal modulation of tumor-infiltrating effector and regulatory T cells. Notably, for the first time, our results demonstrate the reversion of TAMs and improvement of αPD-L1 cancer therapy by synthetic carbohydrate-containing nanomaterials. This research highlights a promising strategy for optimizing immune checkpoint blockade in cancer immunotherapy.