Disruption of the interferon-gamma axis limits chimeric antigen receptor T cell efficacy against acute myeloid leukemia

Despite the success of chimeric antigen receptor (CAR) T cell therapy for treatment of B cell acute lymphoblastic leukemia (B-ALL), its translation to acute myeloid leukemia (AML) has been hindered by limited efficacy and significant toxicity. Interferon-gamma (IFNγ) blockade with emapalumab has recently emerged as a promising strategy to mitigate CAR T cell-related toxicities in B cell malignancies, based on evidence that IFNγ is largely dispensable for optimal CAR T cell activity in B-ALL. Whether IFNγ signaling is similarly non-essential in the AML context remains unclear. Here, we demonstrate that disruption of the IFNγ axis impedes anti-AML CAR T cell function and prevents upregulation of target antigen CD123, the apoptotic mediator Fas, and the adhesion molecule ICAM-1 on AML cells. Conversely, exogenous IFNγ enhances CAR T cell cytotoxicity and increases CAR T cell avidity for AML targets. These findings identify IFNγ as a critical mediator of CAR T cell efficacy against AML by promoting increased target antigen expression, enhanced cytotoxicity, and stable CAR T/tumor interactions. Our results suggest that therapeutic IFNγ blockade, including with emapalumab, may compromise CAR T cell responses in AML and should be approached with caution in this disease context.