Thesis
Promoting antigen presentation in cancer cells through degradation of tumour-associated antigens
- Abstract:
-
In cancer, antigen presentation of tumour-specific antigens (TSAs) and tumour-associated antigens (TAAs) is critical for eliciting T cell-mediated anti-tumour responses. Survivin, an intracellular TAA ubiquitously overexpressed in malignancies, is associated with poor prognosis due to its dual functions in promoting cell proliferation and inhibiting apoptosis. Given the limited clinical success of targeting survivin synthesis, we aim to promote proteasomal degradation of survivin using small-molecule inhibitors and proteolysis targeting chimera (PROTAC) to increase the presentation of survivin epitopes on cancer cells, thereby enhancing T cell recognition and cancer clearance.
We synthesised a library of LQZ-7 analogues and evaluated their potency of survivin inhibition and cytotoxicity. Key residues mediating interactions with survivin were identified, and LQZ-7I emerged as a potent degrader. Using LQZ-7I as the survivin-binding ligand, we developed the first survivin-targeting PROTACs. In a murine in vitro assay, LQZ-7I led to enhanced survivin antigen presentation, whereas human survivin-specific TCR-based studies with PROTAC revealed additional mechanisms impeding antigen presentation in cancer cells.
Our results show that enhancing proteasomal degradation of survivin in cancer cells led to increased antigen presentation and improved T cell-mediated cytotoxicity. Ongoing studies aim to further optimise PROTACs and overcome immune evasion mechanisms to advance the application of targeted protein degradation in cancer immunotherapy.
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Authors
Contributors
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Oncology
- Sub department:
- Oncology
- Research group:
- Jiang Group
- Role:
- Supervisor
- ORCID:
- 0000-0003-2103-6929
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Oncology
- Sub department:
- Oncology
- Research group:
- Ramadan Group
- Role:
- Supervisor
- ORCID:
- 0000-0001-5522-021X
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- NDM Immuno-Oncology
- Research group:
- Gillespie Group
- Role:
- Examiner
- ORCID:
- 0000-0002-1075-870X
- Institution:
- Nanyang Technological University
- Research group:
- Xing Group
- Role:
- Examiner
- ORCID:
- 0000-0002-8391-1234
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
-
English
- Keywords:
- Subjects:
- Deposit date:
-
2025-07-13
- ARK identifier:
Terms of use
- Copyright holder:
- Sichen Liu
- Copyright date:
- 2024
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