Scancell Ltd, Nottingham, UK.
Proteome Science R&D GmbH und Co, Frankfurt am Main, Hessen, Germany.
J Immunother Cancer. 2023 Oct;11(10). doi: 10.1136/jitc-2023-006966.
Post-translational modification of proteins has the potential to alter the ability of T cells to recognize major histocompatibility complex (MHC) class -I and class-II restricted antigens, thereby resulting in altered immune responses. One such modification is carbamylation (homocitrullination) that results in the formation of homocitrulline (Hcit) residues in a non-enzymatic reaction of cyanate with the lysine residues in the polypeptide chain. Homocitrullination occurs in the tumor microenvironment and CD4-mediated immune responses to Hcit epitopes can target stressed tumor cells and provide a potent antitumor response in mouse models.
Homocitrullinated peptides were identified and assessed in vitro for HLA-A2 binding and in vivo in human leukocyte antigen (HLA) transgenic mouse models for immunogenicity. CD8 responses were assessed in vitro for cytotoxicity and in vivo tumor therapy. Human tumor samples were analyzed by targeted mass spectrometry for presence of homocitrullinated peptides.
Homocitrullinated peptides from aldolase and cytokeratin were identified, that stimulated CD8-mediated responses in vivo. Modified peptides showed enhanced binding to HLA-A2 compared with the native sequences and immunization of HLA-A2 transgenic mice generated high avidity modification specific CD8 responses that killed peptide expressing target cells. Importantly, in vivo the homocitrullinated aldolase specific response was associated with efficient CD8 dependent antitumor therapy of the aggressive murine B16 tumor model indicating that this epitope is naturally presented in the tumor. In addition, the homocitrullinated aldolase epitope was also detected in human tumor samples.
This is the first evidence that homocitrullinated peptides can be processed and presented via MHC-I and targeted for tumor therapy. Thus, Hcit-specific CD8 T-cell responses have potential in the development of future anticancer therapy.
蛋白质的翻译后修饰有可能改变 T 细胞识别主要组织相容性复合体（MHC）I 类和 II 类限制抗原的能力，从而导致免疫反应改变。这种修饰之一是氨甲酰化（同型瓜氨酸化），它导致氰酸盐与多肽链中的赖氨酸残基发生非酶反应，形成同型瓜氨酸（Hcit）残基。同型瓜氨酸化发生在肿瘤微环境中，CD4 介导的针对 Hcit 表位的免疫反应可以靶向应激肿瘤细胞，并在小鼠模型中提供有效的抗肿瘤反应。
鉴定同型瓜氨酸化肽并在体外评估其与 HLA-A2 的结合，以及在人类白细胞抗原（HLA）转基因小鼠模型中评估其免疫原性。在体外评估 CD8 反应的细胞毒性，并在体内评估肿瘤治疗。通过靶向质谱分析人类肿瘤样本中同型瓜氨酸化肽的存在。
鉴定出醛缩酶和细胞角蛋白的同型瓜氨酸化肽，这些肽在体内刺激 CD8 介导的反应。与天然序列相比，修饰后的肽显示出增强的与 HLA-A2 的结合，并且 HLA-A2 转基因小鼠的免疫接种产生了高亲和力修饰特异性 CD8 反应，可杀死表达肽的靶细胞。重要的是，体内同型瓜氨酸化醛缩酶特异性反应与侵袭性 B16 肿瘤模型中有效的 CD8 依赖性抗肿瘤治疗相关，表明该表位在肿瘤中自然呈递。此外，还在人类肿瘤样本中检测到同型瓜氨酸化醛缩酶表位。
这是同型瓜氨酸化肽可以通过 MHC-I 加工和呈递并靶向肿瘤治疗的第一个证据。因此，Hcit 特异性 CD8 T 细胞反应有可能开发未来的抗癌治疗方法。
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