Applications open on 14 November and close on 9 January 2023 at 17.00 (GMT)
Professor David Sansom (UCL) and Dr Simon Dovedi (AstraZeneca)
Immunotherapy has revolutionised the treatment of cancer. The 2018 Nobel Prize in medicine to Allison and Honjo recognised this groundbreaking shift in our approach to cancer treatment whereby instead of cytotoxic drugs targeting cancer tissue, antibodies are used to remove the “brakes” on the immune system. This targeting of "immune checkpoints" and not the cancer itself represents a fundamental change in thinking, recognising that cancer can be targeted by the immune system and therefore manipulating the immune response can be highly beneficial. Two main checkpoints have been targeted to date (CTLA-4 and PD-1), whose function is normally to control autoimmune or chronic T cell responses. While blocking these inhibitory mechanisms for the purpose of cancer therapy is highly effective, remarkably little is known regarding how these checkpoints actually work.
The Sansom lab is a world leader in CTLA-4 biology and has shown that CTLA-4 has the ability to capture and destroy its ligands (CD80 and CD86) using a cell-biological process known as Transendocytosis (TE)1. This involves intracellular delivery of CTLA-4 to immune contacts (between T cells and antigen presenting cells) followed by rapid internalisation of the ligand from opposing cells with either recycling or degradation of CTLA-4. We have recently shown for the first time that it is the two ligands for the CTLA-4 pathway (CD80 and CD86) that control this outcome2. While, the basis for this differential control of CTLA-4 fate remains to be established, one of the ligands (CD80) is a homodimer whilst the other (CD86) is a monomer, raising the possibility that such differences may influence CTLA-4 fate.
Interestingly, CD80 also directly interacts with a ligand from the PD-1 pathway (PD-L1) disabling its function. However, this interaction generates a CD80-PD-L1 heterodimer thereby disrupting the normal dimer-dimer interaction between CD80 and CTLA-4. We have now found that CTLA-4 TE can control this interaction by removing CD80 and restoring the availability of PD-L13. A result it appears that that CTLA-4 may interact with at least 3 different ligand species; a CD80 homodimer, CD80-PD-L1 heterodimer and a CD86 monomer all of which may affect its fate.
The aim of the proposed project is therefore to explore how differences in natural ligand interactions in terms of affinity and dimersation states affect the fate of CTLA-4 and compare these with interactions driven by therapeutic antibodies. Indeed, whilst, therapeutic antibodies traditionally have high affinity bivalent interactions, increasingly bispecific and other designs are increasingly being utilised, allowing us to test the impact of valence (e.g. bivalent vs. monovalent) and structure/geometry of these antibody interactions on CTLA-4 biology.
The project presents an opportunity to learn cellular immunology and its application to cancer therapy. The project will involve the use of a variety of molecular cloning techniques, the opportunity to learn CRISPR gene editing and apply biochemistry and cell biology (live cell imaging) approaches to the above problems.
1.Qureshi, O.S., Y. Zheng, et.al., L.S.K. Walker, and D.M. Sansom. 2011. Trans-endocytosis of CD80 and CD86: A molecular basis for the cell extrinsic function of CTLA-4: Science 332:600-603
2.Kennedy A, Waters E, Rowshanravan B, Hinze C, Williams C, Janman D, et al. (2022) Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Nat Immunol. https://doi.org/10.1038/s41590-022-01289-w
3. Kennedy A, Robinson M, Hinze C, Waters E, Williams C, Halliday N, Dovedi SJ, and Sansom DM. (2022)CTLA-4 regulates PD-L1-PD-1 interactions via transendocytosis of CD80 EMBO J. In revision. / https://www.biorxiv.org/content/10.1101/2022.03.28.486104v1
Dovedi, S.J., Elder, M.J., Yang, C., Sitnikova, S.I., Irving, L., Hansen, A., Hair, J., Jones, D.C., Hasani, S., Wang, B., et al. (2021). Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1(+) Activated T Cells. Cancer Discov 11, 1100-1117.
Walker, L.S., and Sansom, D.M. (2015). Confusing signals: Recent progress in CTLA-4 biology. Trends in immunology 36, 63-70.
Rowshanravan, B., Halliday, N., and Sansom, D.M. (2018). CTLA-4: a moving target in immunotherapy. Blood 131, 58-67.