Deciphering the effect of regulatory variants on CD8 T cell response to checkpoint immunotherapy
Inter-individual variation in immune responses means that the same pathogen can lead to vastly different clinical outcomes. Much of this variation is due to genetic causes, and genetically determined differential gene expression is a key driver of phenotypic diversity. We have previously demonstrated that monocyte responses to pathogen related molecules and cytokines are strongly influenced by germline genetic variation, and that many of these regulatory variants are also Genome-wide associated study defined disease risk variants.
Checkpoint immunotherapy has revolutionised the treatment of cancer, although there is marked heterogeneity in clinical benefit and the key determinants of therapeutic utility remain incompletely resolved. Treatment with immunotherapy elicits widespread changes in gene expression, most notably in the CD8 T cell subset. Just as regulatory variants impact immune responses to cytokines and pathogens, it is likely that such variation conditions responses to checkpoint immunotherapy. We are currently investigating this across CD8 T cells from a large cohort of patients.
This project will further characterise regulatory variants found to impact response to checkpoint immunotherapy in CD8 T cells, exploring how they interact with T cell clone size and other features, using molecular biology, immunological and bioinformatic techniques.
You will be taught molecular biology including CRISPR, computational and immunological approaches including handling of single cell sequencing data, flow cytometry and analysis of big datasets.