Discovery and characterisation of HLA-agnostic anti-cancer T-cells

Tan, Li Rong 2026. Discovery and characterisation of HLA-agnostic anti-cancer T-cells. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background - The conventional narrative of tumour elimination emphasises CD8⁺ αβ T-cells recognising tumours via the HLA class I pathway. However, HLA class I downregulation occurs in >40% of cancers, posing a major obstacle to immunotherapy. In addition, HLA restriction limits TCR-T therapy, since even the most common HLA alleles cover only a minority of patients. There is a pressing need for safe anti-cancer TCRs suitable for HLA-agnostic, universal “off-the-shelf” therapies. Loss of β2 microglobulin (β2M), essential for antigen presentation via HLA class I and MHC-like molecules such as CD1 and MR1, is observed in a significant subset of patients. I hypothesised that β2M-negative cancers might provide a ready source of HLA-independent anti-cancer T-cells and TCRs. Methods - I analysed tumour-infiltrating lymphocyte (TIL) products from a patient with β2M-negative metastatic melanoma (NCT00937625) who achieved stable disease after TIL therapy. TCRs were cloned and tested for recognition of multiple cancer types. Genome-wide CRISPR/Cas9 screening and antibodyblocking approaches are being applied to identify the corresponding ligands. Results - Using an autologous melanoma line that lacked functional β2M and therefore could not present antigens via HLA class I, revealed cancer-reactive TILs that expressed γδ TCRs. When transferred into recipient T-cells, these TCRs conferred robust, HLA-independent recognition of diverse cancers, including melanoma, breast, colorectal, lung, pancreatic, and haematological malignancies, consistent with recognition of widely shared non-polymorphic ligands. In vivo persistence and expansion of these γδ T-cells in patients without evident pathology suggest a favourable safety profile. A forward genetic screen has yielded lysis-resistant tumour lines, which are being sequenced to identify molecules required for cancer recognition. Conclusion - These findings demonstrate that β2M-loss cancers expose potent, HLA-independent γδ TCRs with broad-spectrum anti-tumour activity. Defining the ligands they recognise could reveal universal cancer targets and lay the foundation for a new class of safe, off-the-shelf immunotherapies effective in all patients, including those resistant to current T-cell-based treatments.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	26 May 2026
Last Modified:	26 May 2026 13:12
URI:	https://orca.cardiff.ac.uk/id/eprint/187194

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