The role of T cell exhaustion in cutaneous squamous cell carcinoma. (360G-Wellcome-100683_Z_12_Z)

Non-melanoma skin cancer (NMSC) is the most common cancer in the UK. Immunosuppression strongly promotes NMSC (especially squamous cell carcinoma (SCC)) development and metastasis. Skin SCCs are typically surrounded by an immune infiltrate, but persistence of the cancer suggests this immune response is inadequate. Preliminary data showed that CD8+T-cells accumulate in skin SCCs in higher numbers, and have greater expression of the inhibitory receptor PD-1, than CD8+T-cells from blood, and phytoh aemagluttinin-stimulated peritumoral CD8+T-cells proliferated less than those from blood. Therefore we hypothesise that T-cell exhaustion is responsible for defective anti-tumour immunity in SCC. This project will characterise CD8+T-cells from human primary SCCs, examining for phenotypic markers of exhaustion, including PD-1, Tim-3 and BTLA, as well as assessing whether they have impaired effector functions e.g. loss of IL-2, TNF-alpha and IFN-gamma production, and reduced ability to proliferate and degranulate upon stimulation. Factors in the tumour microenvironment that promote T-cell exhaustion (including inhibitory receptor ligand expression, presence of immunosuppressive cytokines and interactions with tumour-associated macrophages) will be studied. In addition, reversibility of T-cell exhaustion will be assessed using pharmacological inhibitors (e.g. anti-PD-1, anti-Tim-3, anti-LAG-3). Ultimately this project will determine whether targeting T-cell exhaustion offers potential for development of immunopharmacologically-based treatments for SCC.