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Study and modification of T-cell receptor structure to enhance anti-tumor activity

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T cell receptors: striking a balance to fight cancer

An effective immune response against tumour cells is critical in the fight to eliminate cancer. Research now shows that cells that can be created to transfer tumour-reactive lymphocytes.

Health

Although the environment surrounding a tumour and other biological factors are important, it is known that cytotoxic CD8+ T-lymphocytes play a key role in the anti-tumour response. As such, adoptive cell transfer of tumour-reactive lymphocytes can effectively be used to 'referee' the regression of large solid tumours in cancer patients. To avoid the need to isolate and produce tumour-reactive lymphocytes already present in the human organism, cells can be engineered to express a tumour-specific T-cell receptor (TCR) mediator. This innovative strategy has been shown to bring about cancer regression in terminal melanoma patients previously unresponsive to other treatments. However, although high-affinity TCR may grant promising cytotoxic ability, going over the top could damage T-cell function. Thus, more information is needed regarding suitable TCR affinity. The Role of TCR affinity project is working to prove that T-cell receptor affinity can influence lymphocyte activity in TCR-transfer treatment. The challenge researchers have set themselves is to define an optimal range of TCR affinity for mounting an efficient cytotoxic anti-tumour response. To test their hypothesis, project partners have to date generated and isolated TCRs and constructed and validated a retroviral platform to study specificity and differentiation of TCR chains. As work continues, the team plans to finalise characterisation of the activity of mutants, test for suitable combinations of mutated alpha and beta chains, and fine-tune its approach to transduction into rat or house mouse splenocytes (white blood cell types in the spleen). Using a melanoma model, Role of TCR affinity researchers will transfer mutant TCR populations of different affinities and analyse resulting activity. This will provide further information on how TCR affinity affects the anti-tumour cytotoxic response. The team expects that a successful project outcome will reveal how the immune system can recognise and eliminate tumour cells in relation to TCR-transfer treatment. This will in turn boost efforts to improve existing immunotherapies by more efficiently targeting cancer cells.

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