Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, China.
Immunology. 2024 Dec;173(4):654-671. doi: 10.1111/imm.13854. Epub 2024 Aug 22.
Personalized neoantigen therapy has shown long-term and stable efficacy in specific patient populations. However, not all patients have sufficient levels of neoantigens for treatment. Although somatic mutations are commonly found in tumours, a significant portion of these mutations do not trigger an immune response. Patients with low mutation burdens continue to exhibit unresponsiveness to this treatment. We propose a design paradigm for neoantigen vaccines by utilizing the highly immunogenic unnatural amino acid p-nitrophenylalanine (pNOPhe) for sequence alteration of somatic mutations that failed to generate neoepitopes. This enhances the immunogenicity of the mutations and transforms it into a suitable candidate for immunotherapy. The nitrated altered epitope vaccines designed according to this paradigm is capable of activating circulating CD8 T cells and inducing immune cross-reactivity against autologous mutated epitopes in different MHC backgrounds (H-2K, H-2K, and human HLA-A02:01), leading to the elimination of tumour cells carrying the mutation. After immunization with the altered epitopes, tumour growth was significantly inhibited. It is noteworthy that nitrated epitopes induce tumour-infiltrating macrophages to differentiate into the M1 phenotype, surprisingly enhancing the MHC II molecule presenting pathway of macrophages. Nitrated epitope-treated macrophages have the potential to cross-activate CD4 and CD8 T cells, which may explain why pNOPhe can enhance the immunogenicity of epitopes. Meanwhile, the immunosuppressive microenvironment of the tumour is altered due to the activation of macrophages. The nitrated neoantigen vaccine strategy enables the design of vaccines targeting non-immunogenic tumour mutations, expanding the pool of potential peptides for personalized and shared novel antigen therapy. This approach provides treatment opportunities for patients previously ineligible for new antigen vaccine therapy.
个体化新生抗原治疗在特定患者群体中显示出长期和稳定的疗效。然而，并非所有患者都有足够水平的新生抗原用于治疗。尽管肿瘤中通常存在体细胞突变，但其中很大一部分突变不会引发免疫反应。突变负担低的患者继续对这种治疗无反应。我们提出了一种新生抗原疫苗的设计范式，利用高度免疫原性的非天然氨基酸对硝基苯丙氨酸（pNOPhe）对未能产生新生表位的体细胞突变进行序列改变。这增强了突变的免疫原性，并将其转化为免疫治疗的合适候选物。根据该范式设计的硝基化改变表位疫苗能够激活循环 CD8 T 细胞，并诱导针对不同 MHC 背景（H-2K、H-2K 和人 HLA-A02:01）自身突变表位的免疫交叉反应，导致携带突变的肿瘤细胞被消除。用改变的表位免疫后，肿瘤生长明显受到抑制。值得注意的是，硝基化表位诱导肿瘤浸润巨噬细胞分化为 M1 表型，出人意料地增强了巨噬细胞 MHC II 分子呈递途径。硝基化表位处理的巨噬细胞有可能交叉激活 CD4 和 CD8 T 细胞，这可以解释为什么 pNOPhe 可以增强表位的免疫原性。同时，由于巨噬细胞的激活，肿瘤的免疫抑制微环境发生改变。硝基化新生抗原疫苗策略能够设计针对非免疫原性肿瘤突变的疫苗，扩大了个性化和共享新型抗原治疗的潜在肽池。这种方法为以前不符合新抗原疫苗治疗条件的患者提供了治疗机会。
