BCR-ABL1 Drives Transcriptional Reprogramming of Chronic Myeloid Leukemia Cells for Immune Evasion Through C/EBPβ.

Emerging immunotherapy holds promise to achieve treatment-free remission (TFR) for chronic myeloid leukemia (CML) patients, the development of which depends on full understanding of mechanisms driving immune evasion. Our current investigation in a mouse CML model revealed dominant presence of neutrophils during CML progression, accompanied by significant reductions and exhaustion of T cells. In coculture, these BCR-ABL1 expressing neutrophil-like CML cells significantly inhibited T cell proliferation. Gene expression profiling revealed that there was a global activation of both neutrophil markers and related immune suppression genes in these CML cells. Correlative analysis revealed strong correlations between the expression of BCR-ABL1 and immune suppression genes, suggesting a potential regulation of those genes by BCR-ABL1. Importantly, we identified CEBPB as a critical transcription factor that directly regulated the expression of master immune modulators TGFB1 and ARG2 through promoter binding, in both human and mouse CML samples. Therefore, blocking BCR-ABL1, or its downstream C/EBPβ, TGF-β and arginase with inhibitors or shRNAs rescued T cell suppression by neutrophil-like CML cells. Accordingly, combination treatment with targeted therapy using ponatinib and immunotherapy with anti-PD1 antibody not only provides rapid remission, but also delayed relapses after treatment discontinuation, justifying combination treatment for TFR of CML.