Vaccines targeting p53 mutants elicit anti-tumor immunity

IF 9.1 1区 医学 Q1 ONCOLOGY
Dafei Chai , Xu Wang , Chunmei Fan , Junhao Wang , Jing Ming Lim , Xinfang Yu , Ken H. Young , Yong Li
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引用次数: 0

Abstract

The p53 tumor suppressor is commonly mutated in cancer; however, there are no effective treatments targeting p53 mutants. A DNA vaccine gWIZ-S237G targeting the p53 S237G mutant, which is highly expressed in A20 murine tumor cells, was developed and administered intramuscularly via electroporation, either alone or in combination with PD-1 blockade. The anti-p53-S237G immunization elicited a robust protective response against subcutaneous A20 tumors and facilitated the infiltration of immune cells including CD8+ T cells, NK cells, and DCs. The vaccine enhanced the induction and maturation of CD11c+, CD103+CD11c+, and CD8+CD11c+ cells, which in turn promoted tumor-specific antibody production, as well as Th1 and CD8+ T cell-mediated immune responses. Several antigenic epitopes of p53-S237G effectively stimulated multifunctional CD8+ T cells to secrete IFN-γ and TNF-α. The vaccine showed long-term anti-tumor effects that were dependent on memory CD8+ T cells. Furthermore, the anti-p53-S237G vaccine exhibited significant protective efficacy in the A20 liver metastasis models. When combined with PD-1 inhibition, the vaccine showed superior inhibition of tumor growth and liver metastasis. Targeting p53 mutants by vaccination represents a potential precision medicine strategy against cancers harboring p53 mutations.
针对p53突变体的疫苗可引发抗肿瘤免疫。
p53肿瘤抑制基因通常在癌症中发生突变;然而,目前尚无针对p53突变体的有效治疗方法。针对A20小鼠肿瘤细胞中高表达的p53 S237G突变体,开发了一种DNA疫苗gWIZ-S237G,并通过电穿孔肌内注射,单独或联合PD1阻断。抗p53- s237g免疫引起了对皮下A20肿瘤的强大保护反应,并促进了包括CD8+ T细胞、NK细胞和dc在内的免疫细胞的浸润。该疫苗增强了CD11c+、CD103+CD11c+和CD8+CD11c+细胞的诱导和成熟,进而促进肿瘤特异性抗体的产生,以及Th1和CD8+ T细胞介导的免疫应答。p53-S237G的几个抗原表位有效刺激多功能CD8+ T细胞分泌IFN-γ和TNF-α。该疫苗显示出依赖于记忆性CD8+ T细胞的长期抗肿瘤作用。此外,抗p53- s237g疫苗在A20肝转移模型中表现出显著的保护作用。当与PD-1抑制剂联合使用时,该疫苗对肿瘤生长和肝脏转移表现出更好的抑制作用。通过疫苗靶向p53突变体代表了一种潜在的精准医学策略,可以对抗含有p53突变的癌症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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