Adoptive T cell therapy is a promising therapeutic strategy against cancer that is being extensively tested in the clinic, with some promising but also disappointing results. It uses adoptively transferred cytotoxic T cells to directly kill tumour cells. Several factors are found to limit this strategy. One of the most important factors is the dysfunction of T cells, which involves their depletion and/or inactivation. Significant advances have been made towards the description of molecular mechanisms responsible for T cell de-activation, but many questions still remain. The goal of this project is to identify genes that inactivate cytotoxic T cells in the early stages of adoptive transfer immunotherapy against a mouse lymphoma model. I will knock out specific genes that are upregulated in mice where the T cells undergo inactivation soon after transfer, but nor in mice where the T cells retain activity. I will then test the effect of each mutation on the activity and anti-tumour efficacy of the mutant T cells. The expectation is that ablating the expression of genes responsible for T cell inactivation will retain their anti-tumour efficacy even in conditions where normal cells do not. My results may identify genes, proteins and regulatory pathways that might be altered during the manufacture of cytotoxic T cells in the clinic to improve the efficacy as adoptive cell therapy in humans.