Uncovering novel negative regulators of T cell immunity to cancer

Cancer is a leading cause of morbidity and mortality worldwide, accounting for 10.0 million deaths globally in 2020 alone. Immunotherapy has revolutionised the way we treat patients with advanced cancer, but a majority of patients receiving existing immunotherapies will not respond to treatment. A large in vivo screen was undertaken to identify host regulators of cancer growth, revealing genetic factors which upon disruption in host tissues prevented metastasis by enhancing immune responses. Amongst the genes identified was TBC1 domain family member 22a, a GTPase mainly expressed in the haematopoietic compartment. New unpublished data show that TBC1 domain family member 22a plays a critical role in driving host susceptibility to cancer metastasis. Genetic deletion of TBC1 domain family member 22a in host tissues of mice results in near complete eradication of lung metastases from intravenously administered wildtype B16 melanoma cells. Expression of TBC1 domain family member 22a is enriched within T cells and prior findings show that human TBC1 domain family member 22a polymorphisms are associated with altered cytokine production. Using TBC1 domain family member 22a knockout mice in conjunction with cutting-edge multi-dimensional immune profiling, this studentship aims to decipher how TBC1 domain family member 22a and its pathway control cancer metastasis. Exploiting expertise at AstraZeneca, we will explore the potential for targeting of TBC1 domain family member 22a endogenously and in the context of CAR-T cell therapy to disrupt immune suppression and enhance therapeutic outcomes in cancer.

Main techniques:

• Cutting-edge mouse genetics and tumour models

• High-dimensional flow cytometry (spectral analysis)

• Single-cell RNA-Sequencing

• Antibody and peptide-MHC tetramer staining

• Intracellular cytokine staining

• Bioinformatics analysis of high-content data analysis

Visit the laboratory website at: http://roychoudhurilab.org

For more information about this project, and for other opportunities to join the laboratory as a PhD student, email [Email Address Removed]