In cancer, persistent antigenic challenge leads to T cells acquiring a hyporesponsive cell state, also referred to as T cell exhaustion. We have previously demonstrated that human CD3
+ T cells repeatedly stimulated in vitro via their TCR, develop phenotypical characteristics of exhausted T cells found in vivo including increased expression of inhibitory receptors PD-1, TIM-3 and LAG3 and diminished responsiveness to dendritic cell activation and cancer cell cytotoxicity. We showed that PD-1 blockade with nivolumab and treatment with an IKZF3 inhibitor, lenalidomide reinvigorated the exhausted T cells. 1 We next wished to evaluate if blocking of IKZF3 during the development of T cell exhaustion could protect them from acquiring the exhausted phenotype and functional hyporesponsiveness.
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