CAR T
Published on July 23, 2025
Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire
by Alex Kadhim
Researchers at the University of Pennsylvania, alongside international collaborators, have identified the transcription factor CEBPA as a crucial regulator of immune recognition in acute myeloid leukemia (AML). Published in Nature Communications (2025), the study demonstrates that CEBPA loss enables AML cells to evade natural killer (NK) cell-mediated cytotoxicity by suppressing key activating ligands. This immune escape mechanism contributes to disease progression and resistance to NK-based therapies, positioning CEBPA as both a biomarker for immune evasion and a potential therapeutic target in AML.
To uncover genes that modulate NK cell recognition of AML, the team conducted a genome-wide CRISPR-Cas9 knockout screen in MOLM13 AML cells co-cultured with primary human NK cells. CEBPA emerged as the top hit whose loss conferred resistance to NK-mediated killing. Follow-up transcriptional profiling (RNA-seq) of CEBPA-deficient AML cells revealed downregulation of NK-activating ligands, including ULBP1 and NECTIN2. Epigenomic analysis using CUT&RUN confirmed that CEBPA directly binds promoter and enhancer regions of these genes and that its absence reduces chromatin accessibility and histone acetylation (H3K27ac) at these loci. Functional assays showed that CEBPA knockout (KO) AML cells induced significantly lower NK cell degranulation (CD107a expression), reduced IFNγ secretion (p < 0.0001), and impaired conjugate formation. In vivo xenograft models validated these findings: NSG mice injected with CEBPA-KO AML cells and treated with adoptively transferred NK cells exhibited markedly reduced survival compared to controls (median 25 vs. 42 days; p < 0.001). Importantly, ectopic expression of ULBP1 or NECTIN2 in CEBPA-KO cells partially restored NK cell killing, demonstrating the causal role of these ligands. Analysis of patient-derived AML samples confirmed that low CEBPA expression correlates with diminished ligand expression and worse clinical response to NK cell therapies.
By defining how CEBPA controls NK ligand expression and AML immunogenicity, this study offers mechanistic insight into immune evasion and therapeutic resistance. It highlights the potential of targeting epigenetic or transcriptional regulators to enhance immunotherapy efficacy, particularly in CEBPA-deficient AML cases that might otherwise fail NK-based treatments.
Reference:
Cheloni G, Karagkouni D, Pita-Juarez Y, et al. Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire. Nat Commun. 2025;16(1):4819. Published 2025 May 23.
http://doi.org/10.1038/s41467-025-59904-x