The clinical progression of cutaneous T cell lymphomas (CTCL) is heterogeneous but the disorder remains largely incurable. One factor that may determine outcome is the nature of the tumour-specific immune response. Several observations indicate that a CTCL-specific immune response can develop but is likely to be suppressed by several mechanisms of tumour evasion. Antibodies such as anti-PD1 or PDL1, which reverse T cell suppression by inhibitory co-stimulatory molecules, are effective in solid tumours and may be introduced in the management of CTCL. However CTCL represent a novel situation in that the tumour cells, being of haemopoietic origin, also express PD ligands. In this fellowship I will undertake a detailed analysis of the reactive T cell infiltrate in patients with CTCL. The aims of the fellowship are to:- - characterise the number, phenotype and functional properties of T cells within the tumour infiltrate of CTCL - define the pattern of expression of co-stimulatory molecules such as PD1 and Tim3 on tumour infiltrating lymphocytes - determine the antigenic specificity of the T cell infiltrate with particular focus on cancer-testis antigens (CTAg) and primary tumour cells - correlate the functional activity of the reactive T cell infiltrate with clinical outcome. Patients will be recruited from the supra-regional CTCL service and blood and skin biopsies taken at different stages of disease. Malignant and reactive T cells will be isolated and examined by multi-parameter flow cytometry, including a complete analysis of co-stimulatory molecule expression. HLA-peptide tetramers will determine the presence of T cells specific for CTAg, and co-cultures used to investigate recognition of tumour cells by the tumour infiltrate. These results will lead to a substantial increase in understanding mechanisms of immune evasion by CTCL and can be used to guide the introduction of a stratified approach to immune-stimulatory antibody therapy.