Kennedy Trust Prize Studentships
Genetic determinants of tertiary lymphoid structures formation in solid tumours
- Project No: KIR-2023/16
- Intake: 2023 KIR Clinical
Tertiary lymphoid structures (TLS) are highly organized aggregates of stromal and immune cells that form in tissues affected by autoimmunity, infections and cancer. TLS might contain ectopic germinal centers (GCs) and are thought to contribute to the local immune responses. Presence of TLS is associated with clinical outcomes in several conditions. For instance, presence of TLS in the affected tissues is associated with severity in immune-mediated diseases . In murine models of viral infections, formation of ectopic GCs facilitates viral clearance in flu-infected lungs . In solid tumors, TLS are associated with longer overall survival and higher rates of response to immune checkpoint inhibitors [3, 4]. For these reasons, TLS are increasingly considered important in shaping the immune context of the tumor microenviroment and possibly in promoting response to cancer immunotherapy.
However, the factors influencing formation of TLS in solid tumors remain substantially unknown. In particular, it is unclear whether TLS formation is mostly influenced by the somatic mutations occurring in the tumor, or by the germline variants inherited by the host. In this project, we will use novel robust markers of TLS and cutting edge computational approaches used in genome-wide association studies  to being addressing this question. The postholder must have a robust understanding of human genetics and a keen interest in cancer immunology. This is mostly a computational project for which previous experience in the use of statistical software such as R or Python is required.
Tertiary lymphoid structures (TLS), transcriptomics, cancer, human genetics, genome-wide association studies (GWAs).
The successful candidate will be embedded within the Kennedy Institute of Rheumatology (KIR), Oxford. The KIR is a world-leading centre in the fields of tissue biology, inflammation, and repair, with a strong emphasis on clinical translation. They will receive supervision and training by an experienced team of scientists interested biology and genetics of TLS in immune-mediated conditions and cancer. They will work closely with collaborators withing the Institute and the wider community in Oxford.
Specific training opportunities/benefits include:
- RNA-sequencing analysis, TLS and cancer genomics, SNPs array data analysis, computational methods for genome-wide association studies;
- Strong translational environment and excellent links with industry;
- Well-established DPhil programme with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists
Highly collaborative environment with expertise ranging from translational immunology to computational biology and genome-wide association studies (GWAs).
- Pipi, Elena, et al. "Tertiary lymphoid structures: autoimmunity goes local." Frontiers in immunology 9 (2018): 1952.
- Adachi, Yu, et al. "Distinct germinal center selection at local sites shapes memory B cell response to viral escape." Journal of Experimental Medicine 212.10 (2015): 1709-1723.
- Helmink, Beth A., et al. "B cells and tertiary lymphoid structures promote immunotherapy response." Nature 577.7791 (2020): 549-555
- Meylan, Maxime, et al. "Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer." Immunity 55.3 (2022): 527-541.
- Lee, James C., Biasci, D., et al. "Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease." Nature genetics 49.2 (2017): 262-268.
Computational Biology, Inflammation Biology, Data Science.