IDENTIFICATION OF MHC PEPTIDES USING MASS SPECTROMETRY FOR NEOANTIGEN DISCOVERY AND CANCER VACCINE DEVELOPMENT.

Immunotherapy with neoantigens presented by major histocompatibility complex (MHC) is one of the most promising approaches in cancer treatment. Using this approach, cancer vaccines can be designed to target tumor-specific mutations that are not found in normal tissues. Clinical trials have demonstrated an increased immune response and eradication of tumors after injecting synthetic peptides selected from the immunopeptidome. Although the sequence of MHC binding peptides can be predicted from genome sequencing and prediction algorithms, this approach results in large numbers of predicted peptides, requiring the confirmation by mass spectrometry (MS) analysis. Identification of MHC peptides by direct MS analysis of immunopeptidome is accurate and sensitive, with tens of thousands of unique peptides potentially identified from either cancer cell line or tumor tissue. Peptides with mutations can also be identified with patient-specific protein databases constructed from genome or transcriptome sequencing data. MS analysis also enables the characterization of the post-translational modifications (PTMs) of those antigens that cannot be predicted. Moreover, PTMs were found to be more efficient in triggering an immune response. In addition to reviewing recent advances in the identification of neoantigens using MS, the techniques for cancer vaccine candidate selection and formulation, vaccine delivery systems, and the potential for use in combination with other therapeutics are also discussed. It is anticipated that MS-based techniques will play an important role in future cancer vaccine development. © 2019 John Wiley & Sons Ltd. Mass Spec Rev 40:110-125, 2021.