Prediction of neo-epitope immunogenicity reveals TCR recognition determinants and provides insight into immunoediting

Abstract

Summary CD8+ T cell recognition of peptide epitopes plays a central role in immune responses against pathogens and tumors. However, the rules that govern which peptides are truly recognized by existing T cell receptors (TCRs) remain poorly understood, precluding accurate predictions of neo-epitopes for cancer immunotherapy. Here, we capitalize on recent (neo-)epitope data to train a predictor of immunogenic epitopes (PRIME), which captures molecular properties of both antigen presentation and TCR recognition. PRIME not only improves prioritization of neo-epitopes but also correlates with T cell potency and unravels biophysical determinants of TCR recognition that we experimentally validate. Analysis of cancer genomics data reveals that recurrent mutations tend to be less frequent in patients where they are predicted to be immunogenic, providing further evidence for immunoediting in human cancer. PRIME will facilitate identification of pathogen epitopes in infectious diseases and neo-epitopes in cancer immunotherapy.

Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner

“…Data were indexed, integrated, and scaled in HKL2000. The SILv44-WT peptide/HLA-A2 structure was solved using the Phaser molecular replacement module in PHENIX using the TCR and peptide/HLA-A2 from the SILv44-T2Met/HLA-A2 structure as separate search models (34). The initial search model for the T4H2 TCR was built with Sculptor in PHENIX using the α-chain of Protein Data Bank (PDB) 3QEU and the β-chain of PDB 4C56 (59,60).…”

“…The PDB IDs for the structures determined here are 6VMC (T4H2-T2Leu/A2), 6VM9 (T4H2-T2Met/A2), 6VMA (T4H2-WT/A2), and 6VM7 (SILv44-WT/A2). The PDB ID of the separately determined SILv44-T2Met/A2 structure used for comparison is 6VM8 (34). equilibration as is standard.…”

“…Although we were unable to crystallize complexes with the R6C12 TCR, we determined structures for T4H2 bound to the WT, T2Met, and T2Leu peptide/ HLA-A2 complexes, as well as SILv44 bound to the WT peptide/ HLA-A2 complex (SI Appendix, Table S4). The structure of SILv44 bound to the T2Met complex has been described separately (34).…”

Pan-cancer landscape of AID-related mutations, composite mutations and its potential role in the ICI response

“…We addressed this by analyzing the neoepitopes that were products of AID activity on the TCGA cohort and on melanoma patients treated with Nivolumab (anti-PD-1) (Riaz et al, 2017). A recent bioinformatic-experimental study using immunogenic and non-immunogenic peptides, experimental testing and X-ray structures showed that TCR binding and recognition improves with the presence of hydrophobic amino acids (aromatic W, F, Y followed by V, L and I) at specific “MIA’’ positions (position P 4 -P 1-Ω ) due to increased structural avidity, stacking interactions, hydrogen bond acceptance and limited rotational freedom with the TCR (Schmidt et al, 2021). Additionally, as a previous study showed that APOBEC promiscuous activity increases neopeptide hydrophobicity (Boichard et al, 2018), we wondered if AID-related mutations led to the production of not only more hydrophobic neoepitope but more “Immunogenic” in terms of amino acid changes (W, F, Y, V, L, I over others) at MIA positions and if these effects were different due to clonality, histology or mutational processes.…”

“…To account for immunogenicity based on prediction of neopeptide TCR recognition and neopeptide HLA binding, PRIME software was run with default parameters. Neoepitopes were classified as “Immunogenic” if having a PRIME %rank score (the fraction of random 700,000 8- to 14-mers that would have a score higher than the peptide provided in input) lower or equal to 0.5% for the corresponding HLA haplotype of the patient where the neopeptide occurred, or as “Non-Immunogenic” otherwise (Schmidt et al, 2021). For simplicity some cosmic signatures were grouped together as: MMR (SBS6, SBS15, SBS20, SBS21, SBS 26 and SBS44); Smoking-associated (SBS4, SBS18, SBS24 and SBS29); POLE (SBS10a, SBS10b and SBS14) and APOBEC (SBS2 and SBS13).…”