INSERM UMR S935, Poitiers and Villejuif, France.
Eur J Immunol. 2012 Jul;42(7):1870-5. doi: 10.1002/eji.201142043.
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem-cell malignancy characterized by the presence of the chimeric BCR-ABL oncoprotein with deregulated tyrosine-kinase (TK) activity. Although conventional T cells are acknowledged as important players in the control of CML, a possible modification of invariant NKT (iNKT) cells, known for their antitumoral activity, has not been established as yet. Here, we showed that the expression of perforin, CD95L, and promyelocytic leukemia zinc finger, a transcription factor required for maintenance of iNKT cell functions, was reduced or suppressed in CML patients at diagnosis, as compared with healthy individuals. The proliferation rate of blood iNKT cells in response to their cognate ligand was likewise diminished. These functional deficiencies were corrected in patients having achieved complete cytogenetic remission following TK inhibitor or IFN-α therapy. iNKT cells from CML patients in the chronic phase did not display increased TK activity, which argued against a direct autonomous action of BCR-ABL. Instead, we found that their anergic status originated from both intrinsic and APC-dependent dysfunctions. Our data demonstrate that chronic phase CML is associated with functional deficiencies of iNKT cells that are restored upon remission. These results suggest a possible contribution to disease control by TK inhibitor therapies.
慢性髓性白血病（CML）是一种克隆性造血干细胞恶性肿瘤，其特征是存在具有失调酪氨酸激酶（TK）活性的嵌合 BCR-ABL 癌蛋白。尽管传统 T 细胞被认为是控制 CML 的重要参与者，但尚未确定其抗肿瘤活性已知的不变自然杀伤 T（iNKT）细胞的可能修饰。在这里，我们表明与健康个体相比，在诊断时 CML 患者的穿孔素、CD95L 和早幼粒细胞白血病锌指（维持 iNKT 细胞功能所必需的转录因子）的表达减少或受到抑制。对其同源配体的血液 iNKT 细胞增殖率也降低了。在接受 TK 抑制剂或 IFN-α 治疗后达到完全细胞遗传学缓解的患者中，这些功能缺陷得到了纠正。慢性期 CML 患者的 iNKT 细胞未显示出增加的 TK 活性，这表明 BCR-ABL 没有直接的自主作用。相反，我们发现它们的无能状态源自内在和 APC 依赖性功能障碍。我们的数据表明，慢性期 CML 与 iNKT 细胞的功能缺陷有关，这些缺陷在缓解时得到恢复。这些结果表明 TK 抑制剂治疗可能对疾病控制有贡献。
