Tumors escape immunosurveillance by overexpressing the proteasome activator REGγ

Abstract

The success of CD8+ T cell based cancer immunotherapy emphasizes the importance of understanding the mechanisms of generation of MHC-I peptide ligands and possible pathways of tumor cell escape from immunosurveillance. Recently, we showed that peptides generated in the nucleus during the pioneer round of mRNA translation (pioneer translation products, or PTPs) can be a potentially important source of tumor specific peptides, given the presence of aberrant splicing and transcription associated with oncogenesis. Here we show that cancer cells up-regulation of the REG{gamma} proteasome regulator results in increased destruction of PTP-derived peptides in the nucleus thus subverting immunosurveillance. These findings add to understanding of the role of REG{gamma} in antigen processing and identify it as a druggable target for improving the efficacy of cancer immunotherapy.\n\nSignificanceWith the clear success of CD8+ T cell based immunotherapy, it is critical to understand i) how tumor cells generate MHC-I peptide antigens? and ii) the various mechanisms used by cancer cells to evade immunosurveillance. One of them is to up-regulate the REG{gamma} proteasome regulator which results in an increase destruction of MHC-I peptides in the nucleus thus subverting immunosurveillance.