Immunotherapy has become an important therapeutic modality for patients undergoing cancer treatment and has vastly improved outcomes for many whose conditions would otherwise be fatal. Unfortunately, a subset of these patients will develop toxic autoimmune side effects to immune checkpoint inhibitor (ICI) treatment. Currently, clinicians have limited tools to identify those individuals at risk of developing severe adverse events, which would allow interventions for such complications to be initiated early in the course of treatment. In this project, a group led by David Serreze and Nadia Rosenthal will seek to understand why these side effects sometimes occur and use the power of genetics to better predict outcomes for patients. They will study cohorts of genetically engineered mice with humanized immune systems to find specific gene variants uniquely contributing ICI-induced type 1 diabetes or myocarditis (heart inflammation), two relatively rare but life-threatening adverse responses to cancer immunotherapy. This project builds on a $2.5 million ASPIRE Award given to The Jackson Laboratory in 2019 aimed at determining how genetics influences immunotherapy response rates. This project will use the same world-renowned mouse models at Jackson Labs to better translate findings in the lab to the clinic.