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 REGγ 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 REGγ in antigen processing and identify it as a druggable target for improving the efficacy of cancer immunotherapy. SignificanceWith 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 REGγ proteasome regulator which results in an increase destruction of MHC-I peptides in the nucleus thus subverting immunosurveillance.Cellular immune responses against cancer cells expressing non-self epitopes require the activation of CD8+ T cells by professional antigen presenting cells (pAPCs), which take up external peptide material and present it on their major histocompatibility complex class I (MHC-I) molecules as part of a process called cross-presentation (1). The MHC-I direct and cross-presentation pathways are fundamental processes for the detection and elimination of cells that pose a threat to the host. In recent years, it has been suggested that peptides that are directly presented to the MHC-I restricted pathway are not derived from the degradation of full-length proteins but from so-called defective ribosomal products, or DRiPs (2). In addition, some MHC-I-bound peptides are generated by cryptic translation, which refers to polypeptides synthesized in the cell via non-conventional translational mechanisms.These are either peptides encoded by introns, intron/exon junctions, 5' and 3' untranslated regions, alternate translational reading frames, or even fusion peptides generated by the proteasome (3-6).These observations have led to a shift in focus towards the notion that the degradation of full-length proteins is not the only critical process for antigen production. More recently, we have shown that the antigen presentation is equivalent whether the peptide is expressed from an intron or from an exon is supported by so-called pioneer translation products (PTPs) (7), which are produced by a translation event distinct from canonical translation prior to mRNA splicing. The PTP model is appealing because it offers an explanation of how the immune system "tolerates" tissue-dependent alternative splicing products. By first examining how direct presentation applies to viral mechanisms of ...