Implications of Targeting Novel Pathways in Exhausted T Cells for Immuno-Oncology Therapeutic Intervention

T cells can develop an exhausted phenotype as a result of prolonged antigen stimulation[1]. This exhausted phenotype can occur in both CD4+ and CD8+ T cells and has been shown to develop within the tumour microenvironment[2] as a potential mechanism by which tumours cells can escape immune surveillance.

Exhausted T cells are characterised by

• Co-expression of checkpoint inhibitors including PD-1, LAG-3 and TIM-3

• Reduced proliferative potential• Reduced ability to express type I cytokines (such as IL-2, IFN-γ and TNF-α)

• Loss of cytotoxic function

Here we describe a in vitro human exhausted T cell model that can be used as a valuable tool to assess the ability of candidate immuno-oncology therapeutics to rescue an exhausted T cell phenotype, restore T cell function and permit tumour cell clearance. In addition to efficacy of anti-PD-1 treatment, we demonstrate the ability of an inhibitor of a novel target to restore effector T cell function.