MR1 Gene and Protein Expression Are Enhanced by Inhibition of the Extracellular Signal-Regulated Kinase ERK.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Daniel Constantin, Vladimir Nosi, Natalie Kehrer, Alessandro Vacchini, Andrew Chancellor, Emmanuel Contassot, Aisha Beshirova, Gennaro Prota, Alexander Navarini, Lucia Mori, Gennaro De Libero
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Abstract

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.

抑制细胞外信号调节激酶 ERK 可增强 MR1 基因和蛋白的表达。
MHC I 类相关分子 MR1 普遍表达,在哺乳动物中高度保守,并在肿瘤细胞中呈现细菌和内源性抗原。这些特征表明,局限于 MR1 的肿瘤特异性 T 细胞可能是新型癌症定向 T 细胞免疫疗法的理想候选者。MR1 蛋白在细胞表面的表达量非常低,这是限制使用 MR1 导向免疫疗法的一个潜在挑战。要克服这一挑战,就必须加深对 MR1 表达调控机制的了解,因为目前人们对此知之甚少。本研究发现 ERK1/2 是 MR1 基因和蛋白表达的负调控因子。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,可增加MR1蛋白的表达和肿瘤反应性T细胞及MR1限制性T细胞的识别。ERK1/2对MR1的抑制是由ELF1转录因子介导的,而ELF1是MR1基因表达所必需的。ERK1/2抑制作用也出现在不同组织来源的癌细胞系、对抑制突变BRAF药物有抗药性的癌细胞系和原发性癌细胞中,使它们成为特异性T细胞的潜在靶标。与肿瘤细胞相反,ERK1/2抑制后,健康细胞的识别能力很差或没有识别能力。这些发现提出了一种药物方法,可以增加肿瘤细胞中MR1蛋白的表达,进而激活MR1受限的T细胞,具有潜在的治疗意义。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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