Identifying the Genetic Basis of Immune Checkpoint Inhibitor Induced Type 1 Diabetes

Immune Checkpoint Inhibitors (ICIs) are increasingly-used antibody-based anti-cancer treatments. ICI therapy works by utilizing antibodies to interrupt inhibitory T cell signaling thereby blocking T cell death and unleashing the activity of the immune system to destroy tumors. An unfortunate side effect of ICI treatment is the occurrence of immune-related adverse events (irAEs), including Type 1 Diabetes (T1D). Through a backcross mapping study utilizing humanized mice, we identified chromosomal regions associated with ICI-induced diabetes in mice. By comparison of our data with genomic regions associated with classical or spontaneous disease and ICI-induced disease, we were able to narrow our list of candidate genes and validate possible causative candidate genes which may play a role in ICI-induced T1D pathogenesis. We found significant differences in gene expression for a set of genes between mouse strains or with ICI-treatment across immune cell populations. Future work will characterize the role of these genes in ICI-induced T1D