Lost in the crowd: identifying targetable MHC class I neoepitopes for cancer immunotherapy

The recent development of checkpoint blockade immunotherapy for cancer has led to impressive clinical results across multiple tumor types. There is mounting evidence that immune recognition of tumor derived MHC class I (MHC-I) restricted epitopes bearing cancer specific mutations and alterations is a crucial mechanism in successfully triggering immune-mediated tumor rejection. Therapeutic targeting of these cancer specific epitopes (neoepitopes) is emerging as a promising opportunity for the generation of personalized cancer vaccines and adoptive T cell therapies. However, one major obstacle limiting the broader application of neoepitope based therapies is the difficulty of selecting highly immunogenic neoepitopes among the wide array of presented non-immunogenic HLA ligands derived from self-proteins. Areas covered: In this review, we present an overview of the MHC-I processing and presentation pathway, as well as highlight key areas that contribute to the complexity of the associated MHC-I peptidome. We cover recent technological advances that simplify and optimize the identification of targetable neoepitopes for cancer immunotherapeutic applications. Expert commentary: Recent advances in computational modeling, bioinformatics, and mass spectrometry are unlocking the underlying mechanisms governing antigen processing and presentation of tumor-derived neoepitopes.