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

Abstract

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.

Keywords

BCR–ABL1 / chronic myeloid leukemia / neutrophils / immune evasion / tumor microenvironment

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