乳腺癌是影响全球女性人口死亡的主要原因之一。尽管治疗方法得到了进步，对疾病的理解也更充分，但治疗患者仍然存在困难。目前，癌症疫苗领域的主要挑战是抗原的可变性，这可能会降低抗原特异性T细胞反应的有效性。过去几十年中，对免疫原抗原靶点的寻找和验证急剧增加，并且随着现代测序技术的出现，允许快速准确地识别肿瘤细胞的新抗原景观，这一领域肯定会不断增长。我们以前已经在临床前模型和识别和选择突变表位变异体方面实施了可变表位库（VEL）作为非常规疫苗策略。在这里，我们使用基于丙氨酸的序列生成了一个9-mer VEL样式的组合类似物库G3d作为新型疫苗免疫原。对这16,000个G3d派生序列的体外分析显示潜在的MHC-I结合体和免疫模拟物。我们展示了对4T1小鼠乳腺癌模型的G3d治疗的抗肿瘤效果。此外，对一组随机选择的G3d派生模拟物进行的两种不同的T细胞增殖筛选试验使得分离出具有差异治疗疫苗有效性的刺激和抑制模拟物。因此，模拟物库是一个有前途的疫苗免疫原，并且是分离分子肿瘤疫苗成分的可靠来源。Copyright © 2023 Elsevier Ltd. All rights reserved.

Breast cancer is one of the leading causes of death that affects the female population worldwide. Despite advances in treatments and a greater understanding of the disease, there are still difficulties in successfully treating patients. Currently, the main challenge in the field of cancer vaccines is antigenic variability which can reduce antigen-specific T- cell response efficacy. The search for and validation of immunogenic antigen targets increased dramatically over the past few decades and, with the advent of modern sequencing techniques, permitting the fast and accurate identification of the neoantigen landscape of tumor cells, will undoubtedly continue to grow exponentially for years to come. We have previously implemented Variable Epitope Libraries (VEL) as an unconventional vaccine strategy in preclinical models and for identifying and selecting mutant epitope variants. Here, we used an alanine-based sequence to generate a 9-mer VEL-like combinatorial mimotope library G3d as a new class of vaccine immunogen. An in silico analysis of the 16,000 G3d-derived sequences revealed potential MHC-I binders and immunogenic mimotopes. We demonstrated the antitumor effect of treatment with G3d in the 4T1 murine model of breast cancer. Moreover, two different T cell proliferation screening assays against a panel of randomly selected G3d-derived mimotopes allowed the isolation of both stimulatory and inhibitory mimotopes showing differential therapeutic vaccine efficacy. Thus, the mimotope library is a promising vaccine immunogen and a reliable source for isolating molecular cancer vaccine components.Copyright © 2023 Elsevier Ltd. All rights reserved.