The allogenic non-proteinogenic amino acid BMAAbased vaccine breaks up the immune tolerance against colorectal cancer

被引：0

作者：

Tian, Baorui ^{[1
]}

Wang, Shijian ^{[1
]}

Ding, Jixuan ^{[1
]}

Qu, Weiao ^{[1
]}

Zhang, Chen ^{[1
]}

Luan, Fangqun ^{[1
]}

Wang, Nan ^{[1
]}

Hou, Yigong ^{[1
]}

Suo, Mengying ^{[1
]}

Liu, Huimin ^{[1
]}

Chen, Yanan ^{[1
]}

Liu, Yanhua ^{[1
]}

Yan, Jie ^{[1
]}

Zhang, Jianbo ^{[2
]}

Li, Jia ^{[1
]}

Wang, Longlong ^{[1
]}

Shi, Yi ^{[1
]}

Xiang, Rong ^{[1
]}

机构：

[1] Nankai Univ, Sch Med, 94 Weijin Rd, Tianjin 300071, Peoples R China

[2] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastrointestinal Surg, 288 Tianwen Rd, Chongqing 400072, Peoples R China

来源：

THERANOSTICS | 2025年 / 15卷 / 07期

基金：

中国国家自然科学基金;

关键词：

Tumor vaccine; beta-N-methylamino-L-alanine; Colorectal cancer; Nanoparticles; PD-1/PD-L1; MICROSATELLITE INSTABILITY; MISINCORPORATION; CELLS;

D O I：

10.7150/thno.104722

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The fundamental issue in immunotherapy is the lack of tumor-specific antigens in most types of tumors, leading to immune tolerance. For approximately 85% of patients with microsatellite stable (MSS) colorectal cancer (CRC), the absence of tumor neoantigens results in poor immunotherapy efficacy. Our previous study demonstrated that the misincorporation of non-proteinogenic proline (Pro) analog azetidine-2-carboxylic acid (AZE) could generate mutated proteins that significantly enhance tumor cell antigenicity and anti-tumor immune responses. Methods: To activate more specific anti-tumor immune responses with fewer side effects, we utilized the non-proteinogenic serine (Ser) analog beta-N-methylamino-L-alanine (BMAA), which can be misincorporated into proteins as a Ser substitute by seryl tRNA synthetase at an appropriate rate. BMAA misincorporated neoantigens were detected using mass spectrometry (MS), and cancer cell-enriched peptides with high antigenicity were selected in a murine CRC model for the preparation of BMAA-based self-assembling nanoparticles (SAN). Single-cell sequencing was performed to analyze immune responses induced by SAN vaccination combined with a toll-like receptor 7 agonist (TLRa) adjuvant and BMAA treatment. Results: SAN-TLRa vaccination with BMAA treatment induced an anti-tumor immune microenvironment. This combination stimulated the generation of specific CD8+T cells and IgG targeting BMAA misincorporated neoepitopes, ultimately promoting immune activation, tumor suppression, and prolonged survival in the CRC murine model. Additionally, BMAA combined with SAN vaccine significantly enhanced the efficacy of the immune checkpoint inhibitor anti-PD-1 antibody. Conclusion: Our findings provide a promising strategy for artificially introducing neoantigens using BMAA, which can break immune tolerance without disrupting systemic immune balance. This approach offers novel avenues for CRC immunotherapy.

引用

页码：3143 / 3158

页数：16