Screening of Neoantigen HLA Complexes

Mutated peptides, known as neoantigens, derived from a patient's cancer genome can be targeted by T-cell immunity. However, identifying which peptides can be presented by MHC molecules and stimulate T cells has proven challenging. Existing algorithms can predict MHC binding but struggle to account for the half-lives of these complexes (a critical immunological parameter called kinetic stability). Enhancing our ability to determine the true stability of neoantigen peptide/MHC complexes is crucial, as only a small fraction of peptides in current vaccines effectively trigger CD8+ T-cell responses.

A study utilized a rapid, high-throughput approach to experimentally measure peptide/HLA thermal stability on a scale needed for analyzing neoantigens from thousands of patients. By combining UV-cleavable peptide/HLA class I complexes with differential scanning fluorimetry, the Tm values of neoantigen complexes were determined. These Tm values were accurate, reproducible, and directly proportional to the complexes' half-lives. When analyzing known HLA-A2–restricted immunogenic peptides, Tm values correlated more strongly with immunogenicity than algorithm-predicted binding affinities. Using temperature stability information can help select neoantigens for cancer vaccines, focusing on mutated peptides most likely to be expressed on the cell surface.

Tm analysis of HLA-A2 complexes containing immunogenic neoantigen peptides