Abstract
Somatic variations are frequent and important drivers in cancers. Amino acid substitutions can yield neoantigens that are detected by the immune system. Neoantigens can lead to immune response and tumor rejection. Although neoantigen load and occurrence have been widely studied, a detailed pan-cancer analysis of the occurrence and characterization of neoepitopes is missing. We investigated the proteome-wide amino acid substitutions in 8-, 9-, 10-, and 11-mer peptides in 30 cancer types with the NetMHC 4.0 software. 11,316,078 (0.24%) of the predicted 8-, 9-, 10-, and 11-mer peptides were highly likely neoepitope candidates and were derived from 95.44% of human proteins. Binding affinity to MHC molecules is just one of the many epitope features. The most likely epitopes are those which are detected by several MHCs and of several peptide lengths. 9-mer peptides are the most common among the high binding neoantigens. 0.17% of all variants yield more than 100 neoepitopes and are considered as the best candidates for any application. Amino acid distributions indicate that variants at all positions in neoepitopes of any length are, on average, more hydrophobic than the wild-type residues. We characterized properties of neoepitopes in 30 cancer types and estimated the likely numbers of tumor-derived epitopes that could induce an immune response. We found that amino acid distributions, at all positions in neoepitopes of all lengths, contain more hydrophobic residues than the wild-type sequences implying that the hydropathy nature of neoepitopes is an important property. The neoepitope characteristics can be employed for various applications including targeted cancer vaccine development for precision medicine.
Highlights
The task of the immune system is to detect and destroy foreign molecules and organisms
Numerous methods have been developed to predict the antigenicity of peptides, especially those binding to major histocompatibility complexes (MHCs) type I molecules[5]
For each amino acid substitutions (AASs), a 21-mer parent peptide was constructed such that the variant position was at the center of the peptide, flanked by ten amino acids on both sides
Summary
The task of the immune system is to detect and destroy foreign molecules and organisms. It is highly likely that cancer tissues include numerous immunogenic proteins because substitutions in the DNA, the most abundant changes in cancers, can lead to amino acid substitutions (AASs) in proteins To use neoantigens for therapeutic purposes, numerous research projects aim at detecting cancer variant peptides for diagnosis and treatment, including vaccination. Numerous methods have been developed to predict the antigenicity of peptides, especially those binding to MHC type I molecules[5]. The performance of these tools varies[6,7] depending on the size and composition of the used benchmark dataset[8]. Feature Number of variants Number of predictions Number of proteins with variants (% proteome) Number of weak binding peptides (%) Number of high binding peptides (%) Number of predicted neoepitopes (%) Number of neoepitopes per protein (max; mean; min) Number of neoepitopes per cancer (max; mean; min) Number of neoepitopes per variant (max; mean; min) Number of proteins with neoepitopes (% all proteins) Number of variants that cause neoepitopes (%)
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