Demonstrating restoration of T cell function in exhausted T cells with IKZF3 small molecule inhibitor, Lenalidomide

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

Here we describe an 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 tumor 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.

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

Exhausted T cells are characterized by the following:

  • 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 an 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 tumor 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.

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