Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA.
Nat Commun. 2023 Jun 23;14(1):3763. doi: 10.1038/s41467-023-39425-1.
Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.
癌细胞中蛋白质磷酸化的改变通常导致磷酸肽新抗原的表面呈现。然而，它们在癌症免疫原性中的作用仍不清楚。在这里，我们描述了一种机制，即 HLA-B*0702 特异性急性髓系白血病磷酸肽新抗原 pMLL (EPR(pS)PSHSM) 被一种称为 TCR27 的同源 T 细胞受体识别，TCR27 是癌症免疫治疗的候选者。我们表明，将磷酸丝氨酸 P 替换为丝氨酸或磷酸模拟物不会影响 pMHC 构象或肽-MHC 亲和力，但会消除 TCR27 依赖性 T 细胞激活，并削弱 TCR27 与 pMHC 之间的结合。在这里，我们描述了 TCR27 和同源 pMHC 的晶体结构、核磁共振产生的界面图谱以及使用信息驱动的蛋白质对接生成的三元复合物。我们的数据表明，表位磷酸基团与 TCR27 之间的非共价相互作用对于 TCR 特异性至关重要。这项研究支持通过靶标扩展和 TCR 优化为癌症患者开发新的治疗选择。
