Mapping the MHC Class I–Spliced Immunopeptidome of Cancer Cells

Abstract

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Response to Comment on “A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands”

“…In general, we do not believe that the reanalysis of our data by Rolfs et al had been performed with the necessary accuracy and that, therefore, their comments are not substantiated. Their conclusions are not only in contrast with that of new studies from various independent groups (6,7) but also in contrast with their own findings that up to 6% (8) of cis-spliced and potentially much higher proportions of trans-spliced peptides (9) may be present in the immunopeptidome.…”

Proteolytic dynamics of human 20S thymoproteasome

“…Our study also shows that 20S t-proteasomes can generate spliced peptides, which are thought to represent a large portion of the MHC-I immunopeptidome, the peptides bound to MHC-I molecules (45)(46)(47). The generation of spliced epitopes by t-and i-proteasomes in the thymus could strongly impinge upon our models of central tolerance and discrimination between self and nonself by our immune system (48).…”

“…Proteasome isoforms overall share a common substrate cleavage-site usage with specific differences. The correlation between the SCSs of the synthetic substrates gp100 201-230 (pink circles), gp100 [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] (blue circles), MBP 102-129 (green circles), and MOG 172-202 (black circles) generated in in vitro digestion kinetics by human 20S s-, i-, or t-proteasomes is shown. The SCSs are compared in proteasomes pairwise.…”

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

“…The remarkable success of T cell-based immunotherapy has ended the debate, clearly establishing the relevance of pioneering work defining tumor-specific peptides in mouse models (Van den Eynde et al, 1995;van der Bruggen et al, 1991). Immunogenic cancer-associated peptides can arise from mutations in tumor cell source genes (Yadav et al, 2014), cellular alterations that enhance transcription or translation of non-tolerized open reading frames (Laumont et al, 2018), and post-translational modifications of peptides (Liepe et al, 2019).…”