Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.
University of Science and Technology of China, Hefei 230026, P. R. China.
ACS Appl Mater Interfaces. 2020 Sep 16;12(37):41127-41137. doi: 10.1021/acsami.0c12734. Epub 2020 Sep 1.
Weak T cell responses and immune checkpoints within tumors could be two key factors for limiting antitumor efficacy in the field of cancer immunotherapy. Thus, the combined strategy of tumor vaccines and immune checkpoint blockade has been widely studied and expected to boost antitumor immune responses. Herein, we first developed a two-barreled strategy to combine the nanovaccine with a gene-mediated PD-L1 blockade. On the one hand, polyethyleneimine (PEI) worked as a vaccine carrier to codeliver the antigen ovalbumin (OVA) and the adjuvant unmethylated cytosine-phosphate-guanine (CpG) to formulate the PEI/OVA/CpG nanovaccine through electrostatic binding, which realized both dendritic cell activation and antigen cross-presentation enhancement. On the other hand, the PD-L1 silence gene was loaded by PEI to form PEI/shPD-L1 complexes, which were further shielded by aldehyde-modified polyethylene glycol (OHC-PEG-CHO) pH-responsive Schiff base bonds. The formed shPD-L1@NPs could decrease PD-L1 expression on the tumor cells. However, such a combined two-barreled strategy improved feebly for tumor inhibition in comparison with monotherapy, exhibiting the antagonistic effect, which might be due to the limited T cell response enhancement in the tumor microenvironment. To solve this problem, we have further developed a three-barreled strategy to combine oral administration of l-arginine, which worked as an amplifier to induce robust T cell response enhancement, without causing the upregulation of other negative immune regulators. Superior antitumor behavior and tumor rechallenge protection were realized by the three-barreled strategy in B16F10-OVA (B16-OVA)-bearing mice. The unique three-barreled strategy we developed might offer a novel clinical therapeutic treatment.
弱的 T 细胞反应和肿瘤内的免疫检查点可能是癌症免疫治疗领域限制抗肿瘤疗效的两个关键因素。因此，肿瘤疫苗和免疫检查点阻断的联合策略已经得到了广泛的研究，并有望增强抗肿瘤免疫反应。在这里，我们首先开发了一种双管齐下的策略，将纳米疫苗与基因介导的 PD-L1 阻断相结合。一方面，聚乙烯亚胺（PEI）作为疫苗载体，共递送抗原卵清蛋白（OVA）和非甲基化胞嘧啶-磷酸-鸟嘌呤（CpG）佐剂，通过静电结合形成 PEI/OVA/CpG 纳米疫苗，实现树突状细胞的激活和抗原交叉呈递增强。另一方面，PD-L1 沉默基因被 PEI 加载形成 PEI/shPD-L1 复合物，然后进一步被醛修饰的聚乙二醇（OHC-PEG-CHO）pH 响应席夫碱键屏蔽。形成的 shPD-L1@NPs 可以降低肿瘤细胞上的 PD-L1 表达。然而，与单药治疗相比，这种联合的双管齐下的策略对肿瘤抑制的改善作用较弱，表现出拮抗作用，这可能是由于肿瘤微环境中 T 细胞反应增强有限。为了解决这个问题，我们进一步开发了一种三管齐下的策略，将左旋精氨酸口服给药，作为增强强大 T 细胞反应的放大器，而不会引起其他负免疫调节剂的上调。在 B16F10-OVA（B16-OVA）荷瘤小鼠中，三管齐下的策略实现了优越的抗肿瘤行为和肿瘤再挑战保护。我们开发的独特的三管齐下的策略可能为临床治疗提供一种新的治疗方法。
