Talk Title:

Coevolution of the cancer genome and MHC in immune surveillance by T cells

Talk Summary:

Antigen presentation via the Major Histocompatibility Complex Class (MHC) is an essential component of anti-tumor immunity induced by immune checkpoint inhibition. MHC molecules expose peptide fragments on the cell surface, allowing T-Cell elimination of cells displaying antigen peptides. Although this system has evolved as a defense against microbial and viral agents, MHC can also trigger elimination of cancerous cells harboring mutant peptides (neoantigens), a process is referred to as immune surveillance. The genomic region encoding the MHC is one of the most variable regions in the human population and each individual carries multiple MHC alleles that define the set of peptides that can be effectively presented for immune surveillance. We previously developed a computational framework to study interactions between inherited MHC genotypes and the mutational landscape of tumors. Studying these interactions across thousands of tumors in The Cancer Genome Atlas has revealed evidence that immune selection mediated through both class I and class II MHC molecules acts on tumors throughout their development. An inverse correlation between effective presentation and driver mutation frequency across tumor cohorts suggests that presentation is a key requirement for host immunity to control emerging tumor cell populations. Factors that impair the effectiveness of MHC presentation, such as somatic alteration to the MHC itself, are associated with an increase in neoantigen burden. These trends provide new clues about the limitations of endogenous antigen presentation that must be overcome to optimize patient responses to immune checkpoint blockade.