Understanding systems and molecular mechanisms underlying cancer immunotherapy for the development of precision immunotherapy with informed strategies
Recent breakthroughs in immunotherapy development have established that anti-tumour immunity is a major exploitable mechanism to fight cancer. Notably, immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies abrogate negative regulatory mechanisms in the T cell system and enhance anti-tumour immune response, and have been clinically approved for various cancer patients including melanoma, renal cell carcinoma, ovarian cancer, and Hodgkin’s disease. Our recent investigation using a single cell technology identified PD-1 and regulatory T cells (Treg) as two major suppressive mechanisms in tumour-infiltrating T cells from melanoma patients (malignant skin cancer) .
PD-1 is a surface protein that has a role in suppressing T cell receptor (TCR) signalling and thereby inhibiting T cell activation. PD-1 is highly expressed in over-activated T cells (often called ‘exhausted T cells’), and inhibits their reactions to antigen. Thus the blocking of PD-1 and its ligand PD-L1/L2 can release the activity of tumour-specific T cells.
Treg specifically express the transcription factor Foxp3 and suppress anti-cancer immunity, and are a promising target for cancer immunotherapy. Importantly, the immune check point inhibitor anti-CTLA4 antibody not only blocks costimulatory signalling (precisely, CD28 signalling), but also depletes regulatory T cells (Treg). However, anti-CTLA-4 increases the T cell responsiveness to not only cancer antigens but also self-antigens, inducing autoimmune reactions.
In order to understand these dynamic processes during anti-tumour immune response, Masahiro Ono and his group developed a new experimental tool for analysing time-dependent changes in antigen-reactive effector T cells and Treg, designated as Timer-of-Cell-Kinetics-and-Activity,Tocky, [2, 3]).
The proposed project aims to increase the precision of cancer immunotherapy by improving the understanding of T cell regulation in animal models and clinical samples using a multidisciplinary approach. The project will use multidisciplinary approaches including Tocky and multidimensional data analysis, and investigate the immunological effects of immunotherapies  on T cell regulation and to the analysis of clinical samples.
Download a PDF of the complete project proposal: https://d1ijoxngr27nfi.cloudfront.net/docs/default-source/studying-at-the-icr/2_ono_melcher_imperial-icr-studentship.pdf?sfvrsn=fe685e69_2
Funding Notes Full funding is available
Candidate profile Candidates must have a first class or upper second class bachelor’s or master’s degree in Life Sciences or Clinical Sciences.
How to apply Full details about these studentship projects, and the online application form, are available on our website, at: www.icr.ac.uk/phds Applications for all projects should be made online. Please ensure that you read and follow the application instructions very carefully.
Closing date: Monday 3rd December 2018
Please apply via the ICR vacancies web portal
email contact: [Email Address Removed]
supervisor emails [Email Address Removed] and [Email Address Removed]
1. Bradley A et al. (2018) Elucidating T cell activation-dependent mechanisms for bifurcation of regulatory and effector T cell differentiation by multidimensional and single cell analysis, Front Immunol, doi 10.3389/fimmu.2018.01444.
2. Bending D et al. (2018) A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo. J Cell Biol, doi 10.1083/jcb.201711048.
3. Bending D et al. (2018) A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme. EMBO J, 10.15252/embj.201899013.
4. Samson A et al. (2018) Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Science Translational Medicine,10(422). doi: 10.1126/scitranslmed.aam7577.