Genetically engineered mouse models (GEMMs) are used to study cancer and how it develops and progresses in the body. These models are designed to mimic key features of human cancer, however their usefulness in research can be limited by the fact that some features are not well represented. In this project, Nikhil Joshi will expand upon two aspects of cancer immunology that are not well represented in current GEMMs, and propose new models that can better capture these features. The first is the phenomenon of “depleted” neoantigens in human cancer, which will be studied through the mechanism of loss of heterozygosity (LOH). The second feature is intratumoral heterogeneity, which is important for understanding how immunogenic clones are selected against in tumor development. For both questions, Joshi and his group will develop novel GEMMs to generate and test hypotheses. In addition to answering fundamental questions about anti-tumor immunity, these GEMMs will serve as valuable preclinical models for stud immunotherapy against heterogeneous tumors, which respond sub-optimally to existing immunotherapies.