B-cell-specific IRF4 deletion accelerates chronic lymphocytic leukemia development by enhanced tumor immune evasion
B-cell-specific IRF4 deletion accelerates chronic lymphocytic leukemia development by enhanced tumor immune evasion
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DOI：
10.1182/blood.2019000973
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发表时间：
2019-11-14
期刊：
影响因子：
20.3
通讯作者：
Egle, Alexander
中科院分区：
文献类型：
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作者：
Asslaber, Daniela;Qi, Yuan;Egle, Alexander
慢性淋巴细胞白血病 (CLL) 是一种异质性疾病，高度依赖于 CLL 细胞与微环境（尤其是 T 细胞）的交互作用。来自 CLL 患者或小鼠 CLL 模型的 T 细胞偏向于经历过抗原的 T 细胞亚群，表明具有一定程度的抗肿瘤识别能力，但它们也会被耗尽，从而阻止有效的抗肿瘤免疫反应。在这里，我们描述了一种独立于 T 细胞耗竭的 CLL 肿瘤免疫逃避的新机制，在 Tcl-1 转基因小鼠中使用 B 细胞特异性删除转录因子 IRF4（干扰素调节因子 4），从而产生与人类疾病高度相似的小鼠 CLL。我们发现，IRF4 缺陷的 Tcl-1 tg 小鼠的 CLL 疾病进展加快，与 T 细胞激活相关基因的严重下调有关，包括参与抗原加工/呈递和 T 细胞共刺激的基因，这大大减少了 T 细胞亚群的偏斜和耗竭。我们在人类疾病中发现了强有力的类比，在独立的 CLL 患者队列中，IRF4 表达低的 CLL 患者预后较差，T 细胞无法偏向经历过抗原的亚群，共刺激能力下降，以及参与 T 细胞激活的基因下调。这些结果具有治疗相关性，因为我们对免疫特权分子机制的发现可能是 CLL 免疫治疗策略失败的原因，并可能导致未来靶向性的改进。
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.