Characterization of cryptic peptides presented by MHC-I

• Applicant: Professor Dr. Florian Erhard
• Subject Area: Bioinformatics and Theoretical Biology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495215642

The recent success of cancer immunotherapies demonstrates that cytotoxic T cells can efficiently recognize and eliminate tumor cells in vivo. Emerging therapies such as adoptive T cell transfer or therapeutic vaccination require effective targets, i.e., peptides that are presented via the major histocompatibility complex class I (MHC-I) on tumor cells. Neoantigens arise due to somatic mutations in tumors and were considered prime candidates. However, despite tremendous efforts, identified neoantigens are scarce. Cryptic peptides, which are translated from non-canonical reading frames, represent an interesting alternative. We recently discovered that cryptic peptides constitute an abundant class in the MHC-I immunopeptidomes of tumors. Besides their immunogenicity and therapeutic potential, this raised many basic questions about how they are translated, processed and presented on MHC-I. For thousands of MHC-I presented peptides identified by us the genomic loci overlap with those of known proteins, but their reading frames are shifted by +/- 1 nucleotides. We will investigate the mechanisms that result in this unexpected large number of frame-shifted peptides. We also demonstrated that the frequency of cryptic peptides in MHC-I immunopeptidomes is highly allotype-dependent: For some allotypes (e.g., HLA-A*03:01, HLA-B*07:02) more than 10% of all presented peptides are cryptic, for others (e.g., HLA-A*02:01, HLA-B*18:01) it is <2%. Here, we aim to elucidate the mechanisms behind this surprising finding and investigate whether stimuli can change these percentages. We will develop and use innovative computational methods to integrate molecular high-throughput data. We will build on our two software tools PRICE and Peptide PRISM to quantify translation and presentation of cryptic peptides. In summary, our work will reveal fundamental mechanisms behind translation and presentation of this enigmatic class of MHC-I epitopes and help to prioritize cryptic peptides as targets for future functional studies.

• DFG Programme: Research Grants