USING DEEP MUTATIONAL SCANNING TO CHARACTERIZE TUMOR-IMMUNE INTERACTIONS

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

Cancer immunotherapy is a new treatment modality that has revolutionized cancer care, providing benefits to many patients who previously had untreatable disease. However, we still do not fully understand how this breakthrough treatment works at a molecular level. Deep mutational scanning (OMS) is a new technique that enables the generation of large-scale libraries of mutants to understand how changes at the sequence level impact downstream protein phenotypes. Unlike previous, targeted mutagenesis techniques which were limited in the number of mutants that could be surveyed, OMS is capable of generating a comprehensive map of all potential amino acid change in a given protein. I will use OMS to profile how alterations to PD1, one of the key targets of cancer immunotherapy, impact myeloid cell function. A key limitation of existing OMS assays is the relatively coarse readouts, such as cell proliferation. In order to generate a richer characterization of each OMS mutant, I will couple it to single-cell RNA sequencing to enable fine grained readouts of cell state. I will then use the resulting data to train a large language model (LLM), a type of mathematical model that is capable of predicting the impacts of immunotherapy on cell state. This fellowship will give me the tools and techniques to advance my career, launching me on the path to becoming an independent investigator at an R 1 institution.