期刊
BLOOD
卷 134, 期 20, 页码 1717-1729出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019000973
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资金
- SCRI-LIMCR GmbH
- Province of Salzburg [20102-P1509466-FPR01-2015, 20102-P1601064-FPR012017]
- Austrian Science Fund FWF [T671B13, P26719-B19, I1299-B21, I3282-B26 (FOR 2036), I2795-B28]
- Paracelsus Medical Private University Salzburg [PMU E-18/28/147-EGA]
- Austrian Science Fund (FWF) [I2795, P26719] Funding Source: Austrian Science Fund (FWF)
Chronic lymphocytic leukemia (CLL) is a heterogenous disease that is highly dependent on a cross talk of CLL cells with the microenvironment, in particular with T cells. T cells derived from CLL patients or murine CLL models are skewed to an antigen-experienced T-cell subset, indicating a certain degree of antitumor recognition, but they are also exhausted, preventing an effective antitumor immune response. Here we describe a novel mechanism of CLL tumor immune evasion that is independent of T-cell exhaustion, using B-cell-specific deletion of the transcription factor IRF4 (interferon regulatory factor 4) in Tcl-1 transgenic mice developing a murine CLL highly similar to the human disease. We show enhanced CLL disease progression in IRF4-deficient Tcl-1 tg mice, associated with a severe downregulation of genes involved in T-cell activation, including genes involved in antigen processing/presentation and T-cell costimulation, which massively reduced T-cell subset skewing and exhaustion. We found a strong analogy in the human disease, with inferior prognosis of CLL patients with low IRF4 expression in independent CLL patient cohorts, failed T-cell skewing to antigen-experienced subsets, decreased costimulation capacity, and downregulation of genes involved in T-cell activation. These results have therapeutic relevance because our findings on molecular mechanisms of immune privilege may be responsible for the failure of immune-therapeutic strategies in CLL and may lead to improved targeting in the future.
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