Abstract
Whole genome/exome sequencing data for tumors are now abundant, and many tumor antigens, especially mutant antigens (neoantigens), have been identified for cancer immunotherapy. However, only a small fraction of the peptides from these antigens induce cytotoxic T cell responses. Therefore, efficient methods to identify these antigenic peptides are crucial. The current models of major histocompatibility complex (MHC) binding and antigenic prediction are still inaccurate. In this study, 360 9-mer peptides with verified immunological activity were selected to construct a prediction of tumor neoantigen (POTN) model, an immunogenic prediction model specifically for the human leukocyte antigen-A2 allele. Based on the physicochemical properties of amino acids, such as the residue propensity, hydrophobicity, and organic solvent/water, we found that the predictive capability of POTN is superior to that of the prediction programs SYPEITHI, IEDB, and NetMHCpan 4.0. We used POTN to screen peptides for the cancer-testis antigen located on the X chromosome, and we identified several peptides that may trigger immunogenicity. We synthesized and measured the binding affinity and immunogenicity of these peptides and found that the accuracy of POTN is higher than that of NetMHCpan 4.0. Identifying the properties related to the T cell response or immunogenicity paves the way to understanding the MHC/peptide/T cell receptor complex. In conclusion, POTN is an efficient prediction model for screening high-affinity immunogenic peptides from tumor antigens, and thus provides useful information for developing cancer immunotherapy.
Highlights
Cancer immunotherapy has achieved great success in several cancer types [1,2,3], durable clinical responses only occur in some patients
By statistically analyzing the differences in the residual properties for each position, we found that many physicochemical properties are significantly different at position 3 (P3) between the immunogenic peptides and the non-immunogenic peptides, which has not been reported before (Table 2) [60]
We hypothesized that the residues at P3 should be small and flexible, which may contribute to the binding of P4–P7 to the major histocompatibility complex (MHC)/peptide/T cell receptor complex [61]
Summary
Cancer immunotherapy has achieved great success in several cancer types [1,2,3], durable clinical responses only occur in some patients. Evidence from patients who responded to immunotherapy suggests that tumor regression is achieved by activating tumor-antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) [4,5,6,7]. Tumor antigens can be classified as tumor-specific antigens, including neoantigens, and as tumor-associated antigens. Neoantigens are exclusively presented on tumor cell surfaces, whereas tumor-associated antigens are highly expressed on tumor cells but are expressed on normal cells at a low level. We still lack knowledge about the key features of immunogenic peptides and efficient methods to screen tumor antigen peptides from a large number of tumor mutations in personalized immunotherapy
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