MR1 gene and protein expression are enhanced by inhibition of the extracellular signal-regulated kinase ERK.
Daniel ConstantinVladimir NosiNatalie KehrerAlessandro VacchiniAndrew ChancellorEmmanuel ContassotAisha BeshirovaGennaro ProtaAlexander A NavariniLucia MoriGennaro De LiberoPublished in: Cancer immunology research (2024)
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.
Keyphrases
- contrast enhanced
- magnetic resonance
- transcription factor
- signaling pathway
- gene expression
- cell proliferation
- magnetic resonance imaging
- pi k akt
- papillary thyroid
- computed tomography
- dna methylation
- immune response
- oxidative stress
- wild type
- long non coding rna
- cell surface
- drug induced
- cell cycle arrest
- metastatic colorectal cancer