β-amino acid substitution in the SIINFEKL antigen alters immunological recognition.

IF 4.4 4区 医学 Q2 ONCOLOGY
Cancer Biology & Therapy Pub Date : 2025-12-01 Epub Date: 2025-04-08 DOI:10.1080/15384047.2025.2486141
Ichwaku Rastogi, John A Mannone, Ruslan Gibadullin, Jena E Moseman, John Sidney, Alessandro Sette, Douglas G McNeel, Samuel H Gellman
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引用次数: 0

Abstract

Background: Peptide vaccines offer a direct way to initiate an immunogenic response to a defined antigen epitope. However, peptide vaccines are unstable in vivo, subject to rapid enzymatic proteolysis. Replacement of an α-amino acid residue with a homologous β-amino acid residue (native side chain, but backbone extended by a single CH2 unit) impairs proteolysis at nearby amide bonds. Therefore, antigen analogues containing α-to-β replacements have been examined for functional mimicry of native all-α antigens. Another group previously took this approach in the ovalbumin (OVA) antigen model by evaluating single α-to-β analogues of the murine major histocompatibility complex (MHC) I-restricted peptide SIINFEKL.

Methods: We re-examined this set of α/β SIINFEKL antigens. We tested the susceptibility to proteolysis in mouse serum and their ability to activate OVA-antigen-specific CD8 T cells in vitro. Additionally, we tested the α/β antigens in vivo for their ability to induce an antigen-specific immunogenic response in naïve mice and in OVA-expressing tumor-bearing mice.

Results: The α/β antigens were comparable to the native antigen in their susceptibility to proteolysis in serum. Each α/β antigen was capable of activating antigen-specific CD8 T cells in vitro. However, antigen-specific CD8 T cells induced against α/β antigens in vivo were not cross-reactive to the native antigen. Moreover, immunization with α/β analogues did not elicit anti-tumor effects in tumor-bearing mice.

Conclusions: We conclude that even though α/β analogues of the SIINFEKL antigen can elicit a T cell-based response, this class of backbone-modified peptides is not promising from the perspective of antitumor vaccine development.

SIINFEKL抗原中的β-氨基酸取代改变了免疫识别。
背景:肽疫苗提供了一种针对特定抗原表位启动免疫原性应答的直接途径。然而,肽疫苗在体内是不稳定的,受到快速的酶蛋白水解。α-氨基酸残基替换为同源β-氨基酸残基(天然侧链,但主链被单个CH2单元延长)会损害附近酰胺键的蛋白水解。因此,含有α-to-β替代物的抗原类似物已被研究用于功能模仿天然全α抗原。另一组先前通过评估小鼠主要组织相容性复合体(MHC) i限制肽SIINFEKL的单个α-to-β类似物,在卵清蛋白(OVA)抗原模型中采用了这种方法。方法:对α/β SIINFEKL抗原进行复检。我们测试了小鼠血清对蛋白水解的敏感性,以及它们在体外激活ova抗原特异性CD8 T细胞的能力。此外,我们在体内测试了α/β抗原在naïve小鼠和表达ova的荷瘤小鼠中诱导抗原特异性免疫原性反应的能力。结果:α/β抗原对血清蛋白水解的敏感性与天然抗原相当。每种α/β抗原均能在体外激活抗原特异性CD8 T细胞。然而,体内针对α/β抗原诱导的抗原特异性CD8 T细胞对天然抗原没有交叉反应。此外,α/β类似物免疫对荷瘤小鼠没有抗肿瘤作用。结论:尽管SIINFEKL抗原的α/β类似物可以引起基于T细胞的应答,但从抗肿瘤疫苗开发的角度来看,这类骨架修饰肽并不具有前景。
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 Biology & Therapy
Cancer Biology & Therapy 医学-肿瘤学
CiteScore
7.00
自引率
0.00%
发文量
60
审稿时长
2.3 months
期刊介绍: Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
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