MHC I 类相关分子 MR1 普遍表达，在哺乳动物中高度保守，并在肿瘤细胞中呈递细菌和内源性抗原。这些特征表明，仅限于 MR1 的肿瘤特异性 T 细胞可能代表新型癌症定向 T 细胞免疫疗法的理想候选者。细胞表面 MR1 蛋白的极低表达是一个潜在的挑战，限制了 MR1 导向的免疫疗法的可能使用。为了克服这一挑战，重要的是增加对调节 MR1 表达的机制的了解，因为目前对此知之甚少。这项研究确定 ERK1/2 是 MR1 基因和蛋白质表达的负调节因子。抑制肿瘤细胞中的 ERK1/2 或用针对突变 BRAF 的特异性药物治疗 BRAF 突变肿瘤细胞会增加 MR1 蛋白的表达以及肿瘤反应性 T 细胞和 MR1 限制性 T 细胞的识别。 MR1 的 ERK1/2 抑制是由 ELF1 转录因子介导的，这是 MR1 基因表达所必需的。 ERK1/2抑制作用也发生在不同组织来源的癌细胞系、对抑制突变BRAF的药物产生耐药性的癌细胞系以及原代癌细胞中，使它们成为特定T细胞的潜在靶标。与肿瘤细胞相比，ERK1/2 抑制后对健康细胞的识别非常差或不存在。这些发现提出了一种增加肿瘤细胞中 MR1 蛋白表达以及随后激活 MR1 限制性 T 细胞的药物方法，并且它们具有潜在的治疗意义。

The MHC class I-related molecule MR1 is ubiquitously expressed, is highly conserved among mammals, and presents bacterial and endogenous antigens in tumor cells. These features indicate that tumor-specific T cells restricted to MR1 may represent ideal candidates for novel cancer-directed T-cell immunotherapy. The very low expression of the MR1 protein at the cell surface is a potential challenge limiting the possible use of MR1-directed immunotherapies. To overcome this challenge, it is important that understanding of the mechanisms regulating MR1 expression is increased, as little is known about this currently. This study identified ERK1/2 as negative regulators of the MR1 gene and protein expression. Inhibition of ERK1/2 in tumor cells or treatment of BRAF-mutant tumor cells with drugs specific for mutated BRAF increased MR1 protein expression and recognition by tumor-reactive and MR1-restricted T cells. The ERK1/2 inhibition of MR1 was mediated by the ELF1 transcription factor, which was required for MR1 gene expression. The effects of ERK1/2 inhibition also occurred in cancer cell lines of different tissue origins, cancer cell lines resistant to drugs that inhibit mutated BRAF, and primary cancer cells, making them potential targets of specific T cells. In contrast to tumor cells, the recognition of healthy cells was very poor or absent after ERK1/2 inhibition. These findings suggest a pharmaceutical approach to increase MR1 protein expression in tumor cells and the subsequent activation of MR1-restricted T cells, and they have potential therapeutic implications.