Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
ACS Appl Mater Interfaces. 2024 Oct 9;16(40):53577-53590. doi: 10.1021/acsami.4c12821. Epub 2024 Sep 30.
Dendritic cells (DCs) within the tumor microenvironment (TME) have an insufficient capacity to activate T cells through antigen presentation. Furthermore, the programmed cell-death ligand 1 (PD-L1), abundantly expressed on tumor-associated DCs, binds the programmed cell-death 1 (PD-1)-positive T cells and suppresses their immune function. The binding of PD-L1 to CD80 (B7.1) on the same DC via -interactions further prevents T cell costimulation through CD28. Here, we present a strategy to simultaneously promote antigen cross-presentation and block the inhibitory interactions of PD-L1 on DCs to amplify T cell-mediated antitumor responses within the TME. Mesoporous silica nanoparticles (MSNPs) were loaded with clotrimazole (CLT) to boost MHC II-mediated antigen presentation by DCs, surface-modified with mannose to target CD206 on DCs, and then decorated with PD-L1 binding peptide (PDL1bp) to block PD-L1-mediated interactions. PDL1bp was cleaved from the mannosylated and CLT-loaded MSNPs (MSNP-MaN/CLT) under conditions simulating the TME and tethered to PD-L1 to reverse CD80 sequestration on DC2.4 cells. The blocking of PD-L1 by PDL1bp-decorated NPs (MSNP-MaN-PDL1bp) increased the cellular interactions between DC2.4 and EL4 T cells and the amount of IL-2 secretion. The MSNP-MaN/CLT were taken up rapidly by DC2.4 cells, promoted MHC II presentation of hen egg lysozyme (HEL), and increased IL-2 production from HEL antigen-primed 3A9 T cells, which was further enhanced by PDL1bp. In vivo investigation revealed that administration of the CLT-loaded and PDL1bp-functionalized MSNPs remarkably inhibited subcutaneous B16-F10 melanoma tumor growth when compared with anti-PD-L1 therapy. MSNP-MaN-PDL1bp/CLT treatment upregulated the levels of effector molecules such as granzyme B and proinflammatory cytokines (IFNγ and INFα) in the tumor tissue, indicating antitumoral T cell responses. This strategy of utilizing nanoparticles to trigger DC activation while promoting T cell stimulation can be used to amplify the antitumor T cell responses and represents a promising alternative to anti-PD-L1 immunotherapy.
肿瘤微环境（TME）中的树突状细胞（DCs）通过抗原呈递激活 T 细胞的能力不足。此外，大量表达于肿瘤相关 DCs 上的程序性死亡配体 1（PD-L1）与 PD-1 阳性 T 细胞结合并抑制其免疫功能。PD-L1 通过 -相互作用与 DC 上的 CD80（B7.1）结合，进一步通过 CD28 阻止 T 细胞共刺激。在这里，我们提出了一种策略，即同时促进抗原交叉呈递并阻断 PD-L1 在 DC 上的抑制性相互作用，以放大 TME 内 T 细胞介导的抗肿瘤反应。介孔硅纳米粒子（MSNPs）负载克霉唑（CLT）以增强 DC 介导的 MHC II 抗原呈递，表面修饰甘露糖以靶向 DC 上的 CD206，然后用 PD-L1 结合肽（PDL1bp）修饰以阻断 PD-L1 介导的相互作用。PDL1bp 在模拟 TME 的条件下从甘露糖化和 CLT 负载的 MSNPs（MSNP-MaN/CLT）中裂解，并与 PD-L1 结合以逆转 DC2.4 细胞上 CD80 的隔离。PDL1bp 修饰的纳米粒子（MSNP-MaN-PDL1bp）阻断 PD-L1 增加了 DC2.4 和 EL4 T 细胞之间的细胞相互作用和 IL-2 的分泌量。MSNP-MaN/CLT 被 DC2.4 细胞迅速摄取，促进鸡卵溶菌酶（HEL）的 MHC II 呈递，并增加 HEL 抗原引发的 3A9 T 细胞的 IL-2 产生，这一作用通过 PDL1bp 进一步增强。体内研究表明，与抗 PD-L1 治疗相比，CLT 负载和 PDL1bp 功能化 MSNPs 的给药显著抑制了皮下 B16-F10 黑色素瘤肿瘤的生长。MSNP-MaN-PDL1bp/CLT 治疗上调了肿瘤组织中效应分子如颗粒酶 B 和促炎细胞因子（IFNγ 和 INFα）的水平，表明抗肿瘤 T 细胞反应。这种利用纳米粒子触发 DC 激活同时促进 T 细胞刺激的策略可用于放大抗肿瘤 T 细胞反应，是抗 PD-L1 免疫疗法的一种有前途的替代方法。
J Immunother Cancer. 2021-5
Proc Natl Acad Sci U S A. 2021-7-27
J Immunother Cancer. 2020-4
Pharmaceutics. 2025-5-4
Zotero 插件