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

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.

Bulk RNA-sequencing data analyzed in this study are available in the NCBI Gene Expression Omnibus (GEO) database under accession number GSE159991. All other data generated during this study are available from the corresponding author upon reasonable request.

IFNγ signaling promotes CAR T cell activity against AML by enhancing antigen expression and immune synapse formationIFNγ blockade may compromise CAR T cell efficacy in AML.