Recent advances in immunopeptidomic-based tumor neoantigen discovery

The role of aberrantly expressed proteins in tumors in driving immune-mediated control of cancer has been well documented for more than five decades. Today, we know that both aberrantly expressed normal proteins as well as mutant proteins (neoantigens) can function as tumor antigens in both humans and mice. Next-generation sequencing (NGS) and high-resolution mass spectrometry (MS) technologies have made significant advances since the early 2010s, enabling detection of rare but clinically relevant neoantigens recognized by T cells. MS profiling of tumor-specific immunopeptidomes remains the most direct method to identify mutant peptides bound to cellular MHC. However, the need for use of large numbers of cells or significant amounts of tumor tissue to achieve neoantigen detection has historically limited the application of MS. Newer, more sensitive MS technologies have recently demonstrated the capacities to detect neoantigens from fewer cells. Here, we highlight recent advancements in immunopeptidomics-based characterization of tumor-specific neoantigens. Various tumor antigen categories and neoantigen identification approaches are also discussed. Furthermore, we summarize recent reports that achieved successful tumor neoantigen detection by MS using a variety of starting materials, MS acquisition modes, and novel ion mobility devices.