Host genetic factors modulate anti-tumor immunity and immunotherapy responses

Abstract 

Inter-individual variability in anti-tumor immune responses and clinical benefit from immunotherapy cannot be fully explained by tumor-intrinsic features such as mutation burden or oncogenic drivers alone. Increasing evidence from human genetics and functional genomics indicates that host germline variation plays a critical and under-appreciated role in shaping tumor–immune interactions across cancers. In this talk, I will present work exploring how inherited genetic variation modulates tumor evolution, immune recognition, and response to immune checkpoint blockade (ICB). We initially focused on the role of inter-individual variation in HLA genotype in anti-tumor immunity. Subsequently we have extended our analyses to more broadly investigate inherited immune traits on anti-tumor immune responses using interpretable machine learning approaches. Our models implicate genes involved in antigen presentation, innate immune function and metabolic dependencies of immune cells as determinants of effective anti-tumor immunity. Furthermore, our models suggest that CD4 T cells can mediate ICB response in tumors that have lost MHC I. Collectively, this work provides a roadmap for personalizing immunotherapy.

Bio

Dr. Carter is a Professor in the Department of Medicine and Division of Genomics and Precision Medicine. The Carter Lab develops and applies computational and machine learning approaches to improve the mechanistic understanding of how genetic variation contributes to cellular and disease phenotypes toward applications in precision medicine. Dr. Carter is a member of the UCSD Institute for Genomic Medicine, the Bioinformatics and Systems Biology Program and the Moores Cancer Center. She is an NIH Director’s Early Independence Awardee, a Mark Foundation Emerging Leader and Jaime Wyatt Miller Fellow, a CIFAR Azrieli Global Scholar and a Siebel Scholar.