Enhancing proteasomal processing improves survival for a peptide vaccine used to treat glioblastoma
Enhancing proteasomal processing improves survival for a peptide vaccine used to treat glioblastoma
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DOI：
10.1126/scitranslmed.aax4100
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发表时间：
2021-06-16
影响因子：
17.1
通讯作者：
Wong, Albert J.
中科院分区：
文献类型：
--
作者：
Fidanza, Mario;Gupta, Puja;Wong, Albert J.
尽管其在抗原呈递中发挥重要作用，但增强蛋白酶体加工是改进疫苗的一种尚未开发的策略。 pepVIII 是一种针对 EGFRvIII 的抗癌疫苗，已在多项针对胶质母细胞瘤的试验中进行了测试。我们通过计算机和实验检查了 20 种肽，结果表明酪氨酸取代 (Y6-pepVIII) 可最大限度地提高小鼠皮下肿瘤模型中的蛋白酶体裂解和存活率。在颅内神经胶质瘤模型中，与对照动物和接种 pepVIII 的小鼠相比，Y6-pepVIII 的中位生存期分别提高了 62% 和 31%。 Y6-pepVIII 疫苗接种改变了肿瘤浸润淋巴细胞亚群和瘤内 T 细胞上 PD-1 的表达。与抗 PD-1 疗法相结合，治愈了 45% 的 Y6-pepVIII 疫苗接种小鼠，但对 pepVIII 治疗的小鼠无效。对蛋白酶体消化的 pepVIII 和 Y6-pepVIII 进行液相色谱-串联质谱分析表明，大多数片段相似，但在 Y6-pepVIII 消化物中更丰富，并且 77% 来自蛋白酶体催化的肽剪接 (PCPS)。我们鉴定了 10 种结合人和鼠 MHC I 类的肽。其中 9 种是 PCPS 产物，只有一种肽与 EGFRvIII 共线，表明 PCPS 片段可能是 MHC I 类识别的组成部分。尽管与 EGFRvIII 不共线，但所测试的三种 PCPS 产品中的两种在作为疫苗独立施用时能够提高存活率。我们假设对疫苗的免疫反应代表了多种 PCPS 和线性产品的集体贡献。我们的工作提出了一种增加疫苗蛋白酶体加工的策略，从而增强免疫反应并提高小鼠的存活率。
Despite its essential role in antigen presentation, enhancing proteasomal processing is an unexploited strategy for improving vaccines. pepVIII, an anticancer vaccine targeting EGFRvIII, has been tested in several trials for glioblastoma. We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model in mice. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti-PD-1 therapy cured 45% of the Y6-pepVIII-vaccinated mice but was ineffective for pepVIII-treated mice. Liquid chromatography-tandem mass spectrometry analysis of proteasome-digested pepVIII and Y6-pepVIII revealed that most fragments were similar but more abundant in Y6-pepVIII digests and 77% resulted from proteasome-catalyzed peptide splicing (PCPS). We identified 10 peptides that bound human and murine MHC class I. Nine were PCPS products and only one peptide was colinear with EGFRvIII, indicating that PCPS fragments may be a component of MHC class I recognition. Despite not being colinear with EGFRvIII, two of three PCPS products tested were capable of increasing survival when administered independently as vaccines. We hypothesize that the immune response to a vaccine represents the collective contribution from multiple PCPS and linear products. Our work suggests a strategy to increase proteasomal processing of a vaccine that results in an augmented immune response and enhanced survival in mice.