The proteasome immunosubunits,PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐126‐35‐specific T‐cell recognition

The immunodominant MART‐1_26(27)‐35 epitope, liberated from the differentiation antigen melanoma antigen recognized by T cells/melanoma antigen A (MART‐1/Melan‐A), has been frequently targeted in melanoma immunotherapy, but with limited clinical success. Previous studies suggested that this is in part due to an insufficient peptide supply and epitope presentation, since proteasomes containing the immunosubunits β5i/LMP7 (LMP, low molecular weight protein) or β1i/LMP2 and β5i/LMP7 interfere with MART‐1_26‐35 epitope generation in tumor cells. Here, we demonstrate that in addition the IFN‐γ‐inducible proteasome subunit β2i/MECL‐1 (multicatalytic endopeptidase complex‐like 1), proteasome activator 28 (PA28), and ER‐resident aminopeptidase 1 (ERAP1) impair MART‐1_26‐35 epitope generation. β2i/MECL‐1 and PA28 negatively affect C‐ and N‐terminal cleavage and therefore epitope liberation from the proteasome, whereas ERAP1 destroys the MART‐1_26‐35 epitope by overtrimming activity. Constitutive expression of PA28 and ERAP1 in melanoma cells indicate that both interfere with MART‐1_26‐35 epitope generation even in the absence of IFN‐γ. In summary, our results provide first evidence that activities of different antigen‐processing components contribute to an inefficient MART‐1_26‐35 epitope presentation, suggesting the tumor cell's proteolytic machinery might have an important impact on the outcome of epitope‐specific immunotherapies.     

The ubiquitin proteasome system in neurodegenerative diseases: Culprit,accomplice or victim?

A shared hallmark for many neurodegenerative disorders is the accumulation of toxic protein species which is assumed to be the cause for these diseases. Since the ubiquitin proteasome system (UPS) is the most important pathway for selective protein degradation it is likely that it is involved in the aetiology neurodegenerative disorders. Indeed, impairment of the UPS has been reported to occur during neurodegeneration. Although accumulation of toxic protein species (amyloid β) are in turn known to impair the UPS the relationship is not necessarily causal. We provide an overview of the most recent insights in the roles the UPS plays in protein degradation and other processes. Additionally, we discuss the role of the UPS in clearance of the toxic proteins known to accumulate in the hallmarks of neurodegenerative diseases. The present paper will focus on critically reviewing the involvement of the UPS in specific neurodegenerative diseases and will discuss if UPS impairment is a cause, a consequence or both of the disease.     

Antigen discovery for the development of cancer immunotherapy

Central to successful cancer immunotherapy is effective T cell antitumor immunity. Multiple targeted immunotherapies engineered to invigorate T cell-driven antitumor immunity rely on identifying the repertoire of T cell antigens expressed on the tumor cell surface. Mass spectrometry-based survey of such antigens (“immunopeptidomics”) combined with other omics platforms and computational algorithms has been instrumental in identifying and quantifying tumor-derived T cell antigens. In this review, we discuss the types of tumor antigens that have emerged for targeted cancer immunotherapy and the immunopeptidomics methods that are central in MHC peptide identification and quantification. We provide an overview of the strength and limitations of mass spectrometry-driven approaches and how they have been integrated with other technologies to discover targetable T cell antigens for cancer immunotherapy. We highlight some of the emerging cancer immunotherapies that successfully capitalized on immunopeptidomics, their challenges, and mass spectrometry-based strategies that can support their development.