Elucidating the Roles of Novel Genes in MHC-I Presentation

Abstract

The major histocompatibility complex class I (MHC-I) antigen presentation pathway is necessary for the immune system to be able to detect, control, and eliminate cancers. MHC-I binds oligopeptides derived from cellular proteins and presents them on the cell surface to CD8+ T cells. Consequently, the CD8+ T cells can monitor whether any cells are making abnormal proteins and, if so, can destroy those cells. Because MHC-I presentation is not essential for cell viability, immune selection pressure often leads to cancers that are MHC-I low as they can better evade CD8+ T cell recognition. It is, therefore, important to fully understand the mechanisms of MHC-I presentation as this will identify new ways to target and exploit the pathway for cancer therapeutics. Although several components of the MHC-I pathway have already been characterized, some knowledge gaps remain. Unbiased forward genetic screens from our lab identified some novel gene candidates, such as IRF2, which positively regulate MHC-I presentation. In this dissertation, I will reveal which antigen presentation pathway genes are transcriptionally controlled by IRF2 and contribute to the MHC-I presentation deficiency observed in cells lacking IRF2 and I will also show that IRF2 negatively regulates PD-L1 expression. By influencing both MHC-I antigen presentation and PD-L1 expression in this manner, cancers lacking IRF2 (of which there are many) are both harder to see and more difficult to eliminate.