Suckling Richard J, Pamukcu Cevriye, Simmons Robert Alan, Fonseca Daniel, Grant Emma, Harrison Rory, Shaikh Saher A, Khanolkar Rahul C, Ghadbane Hemza, Creese Andrew, Hock Miriam, Gligoris Thomas G, Lepore Marco, Karuppiah Vijaykumar, Salio Mariolina
Immunocore Ltd., Abingdon, United Kingdom.
Front Immunol. 2025 Mar 26;16:1547664. doi: 10.3389/fimmu.2025.1547664. eCollection 2025.
The MHC-class-I-related molecule MR1 presents small metabolites of microbial and self-origin to T cells bearing semi-invariant or variant T cell receptors. One such T cell receptor, MC.7.G5, was previously shown to confer broad MR1-restricted reactivity to tumor cells but not normal cells, sparking interest in the development of non-MHC-restricted immunotherapy approaches.
METHODS/RESULTS: Here we provide cellular, biophysical, and crystallographic evidence that the MC.7.G5 TCR does not have pan-cancer specificity but is restricted to a rare allomorph of MR1, bearing the R9H mutation.
Our results underscore the importance of in-depth characterization of MR1-reactive TCRs against targets expressing the full repertoire of MR1 allomorphs.
主要组织相容性复合体 I 类相关分子 MR1 将微生物来源和自身来源的小分子代谢产物呈递给带有半不变或可变 T 细胞受体的 T 细胞。此前已表明，一种这样的 T 细胞受体 MC.7.G5 赋予对肿瘤细胞而非正常细胞的广泛 MR1 限制性反应性，这引发了对开发非 MHC 限制性免疫治疗方法的兴趣。
方法/结果：在此，我们提供细胞、生物物理和晶体学证据，证明 MC.7.G5 TCR 不具有泛癌特异性，而是限于带有 R9H 突变的罕见 MR1 同种异型。
我们的结果强调了针对表达 MR1 同种异型完整库的靶标深入表征 MR1 反应性 TCR 的重要性。
