Brain Tumor Research Laboratory.
Department of Neurosurgery.
J Immunother. 2021 May 1;44(4):151-161. doi: 10.1097/CJI.0000000000000359.
The promising immunotherapy effects of a multiple antigenic peptide on glioblastoma (GBM) in a previous study encourage the use of adjuvants to enhance its therapeutic efficacy. Among adjuvants, pan HLA-DR-binding epitope (PADRE) and anti-programmed cell death protein 1 (anti-PD1) have potentially been tested for cancer immunotherapy. Therefore, here we evaluated the ability of PADRE and anti-PD1 to enhance the function of the branched multipeptide against GBM. The potential utility of tumor-associated antigens (ErbB-2 and WT-1) targeting GBM with HLA-A24 was confirmed and a branched multipeptide was constructed from these antigens. The effects of the branched multipeptide and PADRE on immunophenotyping and polarized Th cytokine production in dendritic cells were clarified. The expression of PD1 on T cells and PDL1 on GBM cells was also investigated. The interferon-γ enzyme-linked immunospot and lactate dehydrogenase release assays were performed to determine the function of GBM peptide antigen-specific cytotoxic T cells against GBM cells. Overall, this study showed that both ErbB-2 and WT-1 are potential candidates for branched multipeptide construction. The branched multipeptide and PADRE enhanced the expression of major histocompatibility complex and co-stimulatory molecules and the production of polarized Th1 cytokines in dendritic cells. The increase in the number of interferon-γ+ effector T cells was consistent with the increase in the percentage specific lysis of GBM target cells by GBM peptide antigen-specific cytotoxic T cells in the presence of the branched multipeptide, PADRE, and anti-PD1. Our study suggests the combination of branched multipeptide and adjuvants such as PADRE and anti-PD1 can potentially enhance the effects of immunotherapy for GBM treatment.
先前的研究表明，多种抗原肽对胶质母细胞瘤（GBM）具有有前景的免疫治疗效果，这促使人们使用佐剂来增强其治疗效果。在佐剂中，泛 HLA-DR 结合表位（PADRE）和抗程序性细胞死亡蛋白 1（抗 PD1）已被潜在地用于癌症免疫治疗。因此，在这里我们评估了 PADRE 和抗 PD1 增强分枝多肽对 GBM 作用的能力。已证实针对 HLA-A24 的 GBM 的肿瘤相关抗原（ErbB-2 和 WT-1）具有靶向性，并构建了来自这些抗原的分枝多肽。阐明了分枝多肽和 PADRE 对树突状细胞免疫表型和极化 Th 细胞因子产生的影响。还研究了 T 细胞上的 PD1 和 GBM 细胞上的 PDL1 的表达。通过干扰素-γ酶联免疫斑点和乳酸脱氢酶释放试验测定了针对 GBM 细胞的 GBM 肽抗原特异性细胞毒性 T 细胞对 GBM 细胞的功能。总的来说，这项研究表明，ErbB-2 和 WT-1 都是分枝多肽构建的潜在候选物。分枝多肽和 PADRE 增强了树突状细胞主要组织相容性复合体和共刺激分子的表达以及极化 Th1 细胞因子的产生。分枝多肽、PADRE 和抗 PD1 存在时，干扰素-γ+效应 T 细胞数量的增加与 GBM 肽抗原特异性细胞毒性 T 细胞对 GBM 靶细胞的特异性溶解百分比的增加一致。我们的研究表明，分枝多肽与佐剂（如 PADRE 和抗 PD1）的组合可能增强免疫疗法治疗 GBM 的效果。
