Children's Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Int J Mol Sci. 2022 Oct 18;23(20):12444. doi: 10.3390/ijms232012444.
Cancer is a leading cause of death worldwide. The search for innovative therapeutic approaches is a principal focus of medical research. Vaccine strategies targeting a number of tumor-associated antigens are currently being evaluated. To date, none have garnered significant success. Purportedly, an immunosuppressive tumor microenvironment and the accumulation of regulatory T cells contribute to a lack of tumor vaccine efficacy. Aspartyl/asparaginyl β-hydroxylase (ASPH), a promising therapeutic target, is overexpressed in a variety of malignant tumors but is expressed negligibly in normal tissues. Computer analysis predicted that ASPH expresses four peptide sequences (epitopes) capable of stimulating regulatory T cell activity. The abolition of these putative regulatory T cell epitopes increased the CD4 and CD8 effector T cell responses to monocyte-derived dendritic cells pulsed with a modified, epitope-depleted version of ASPH in an ex vivo human lymphoid tissue-equivalent coculture system while simultaneously decreasing the overall number of FoxP3 regulatory T cells. These findings suggest that the efficacy of all new vaccine candidates would profit from screening and eliminating potential tolerogenic regulatory T cell epitopes.
癌症是全球主要的死亡原因之一。寻找创新的治疗方法是医学研究的主要重点。目前正在评估针对多种肿瘤相关抗原的疫苗策略。迄今为止，没有一种方法取得了显著的成功。据称，免疫抑制性肿瘤微环境和调节性 T 细胞的积累导致肿瘤疫苗疗效不佳。天冬氨酰/天冬酰胺 β-羟化酶 (ASPH) 是一种很有前途的治疗靶点，在多种恶性肿瘤中过度表达，但在正常组织中表达可忽略不计。计算机分析预测，ASPH 表达四个能够刺激调节性 T 细胞活性的肽序列（表位）。在体外人淋巴组织等效共培养系统中，用修饰的、表位缺失的 ASPH 脉冲单核细胞来源的树突状细胞时，消除这些潜在的调节性 T 细胞表位增加了 CD4 和 CD8 效应 T 细胞的反应，同时减少了 FoxP3 调节性 T 细胞的总数。这些发现表明，所有新疫苗候选物的疗效都将受益于筛选和消除潜在的耐受调节性 T 细胞表位。
