Optimisation and design of T cell receptors through artificial evolution
Lead Research Organisation:
University College London
Department Name: CoMPLEX
Abstract
The design of novel T cell receptors (TCRs) has become an emergent strategy for developing new forms of immunotherapy, particularly for the treatment of patients with cancer. Structure-guided rational design through the careful selection and modification of certain amino acids has previously been shown to produce TCR structures with altered antigen binding affinities and specificities. The aim of this project is to generalise this rational design process by developing an optimisation algorithm to artificially evolve populations of TCRs. TCR properties will be altered through random amino acid mutation, and the most promising candidates will be retained for further evolution in a process that computationally mimics natural selection. The output should be a new population of TCRs that have been enhanced in their ability to recognise a given antigen.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509577/1 | 01/10/2016 | 24/03/2022 | |||
| 1918204 | Studentship | EP/N509577/1 | 01/10/2016 | 25/12/2020 | Thomas Peacock |
| Description | Two papers have been published (one as co-first author) that relate to a software platform I maintain and develop for the lab group. The Decombinator platform is an in-house software pipeline used by our research group, and by numerous other research groups, to identify and analyse T cell receptor (TCR) sequences within bulk RNA sequence data. While not focused on structure or optimisation of TCRs, collaboration on the first of these projects has elucidated new information on the response of the immune system to lung cancer [1]. The second gives detailed information on the experimental and computation protocol for running the Decombinator pipeline that should be useful to other research groups [2]. [1] Joshi, K., Robert de Massy, M., Ismail, M. et al. Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer. Nat Med 25, 1549-1559 (2019). [2] Uddin I, Woolston A, Peacock T, et al. Quantitative analysis of the T cell receptor repertoire. Methods in Enzymology 629, 465-492 (2019). |
| Exploitation Route | The research on the immune response and lung cancer is ongoing, as more data is collected as part of the TRACERx project. There are many potential ways to explore this new data that will no doubt result in exciting new findings in the field. Work is already ongoing to isolate TCRs known to respond to a known tumour neoantigen, and to test and optimise that TCR experimentally. Structural modelling and structure guided design could have a role to play in this process. Work is also ongoing to improve the Decombinator platform. We hope to formally publish the changes to the software in the coming months. |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| Description | Decombinator User Workshop |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | A workshop to explain the theory, installation and running of the Decombinator software pipeline that is developed and maintained within our research group. The software is a popular cutting-edge tool for the identification and analysis of T cell receptor (TCR) sequences within bulk RNA data. The workshop consisted of a 2 hour presentation and practical session aimed at postgraduate researchers and research group PIs, with the aim of allowing them to run the software suite independently for within their own research. |
| Year(s) Of Engagement Activity | 2019 |