Tumor Immunology, Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
J Exp Med. 2013 Mar 11;210(3):605-21. doi: 10.1084/jem.20121229. Epub 2013 Feb 11.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia arising from the oncogenic break point cluster region/Abelson murine leukemia viral oncogene homolog 1 translocation in hematopoietic stem cells (HSCs), resulting in a leukemia stem cell (LSC). Curing CML depends on the eradication of LSCs. Unfortunately, LSCs are resistant to current treatment strategies. The host's immune system is thought to contribute to disease control, and several immunotherapy strategies are under investigation. However, the interaction of the immune system with LSCs is poorly defined. In the present study, we use a murine CML model to show that LSCs express major histocompatibility complex (MHC) and co-stimulatory molecules and are recognized and killed by leukemia-specific CD8(+) effector CTLs in vitro. In contrast, therapeutic infusions of effector CTLs into CML mice in vivo failed to eradicate LSCs but, paradoxically, increased LSC numbers. LSC proliferation and differentiation was induced by CTL-secreted IFN-γ. Effector CTLs were only able to eliminate LSCs in a situation with minimal leukemia load where CTL-secreted IFN-γ levels were low. In addition, IFN-γ increased proliferation and colony formation of CD34(+) stem/progenitor cells from CML patients in vitro. Our study reveals a novel mechanism by which the immune system contributes to leukemia progression and may be important to improve T cell-based immunotherapy against leukemia.
慢性髓系白血病（CML）是一种克隆性造血前体细胞肿瘤，起源于造血干细胞（HSCs）中的致癌断点簇区/Abelson 鼠白血病病毒致癌基因同源物 1 易位，导致白血病干细胞（LSC）。治愈 CML 取决于 LSCs 的根除。不幸的是，LSCs 对当前的治疗策略具有抗性。人们认为宿主的免疫系统有助于控制疾病，并且正在研究几种免疫疗法策略。然而，免疫系统与 LSCs 的相互作用尚未得到明确界定。在本研究中，我们使用小鼠 CML 模型表明，LSCs 表达主要组织相容性复合体（MHC）和共刺激分子，并在体外被白血病特异性 CD8（+）效应 CTL 识别和杀死。相比之下，体内输注效应 CTL 到 CML 小鼠中未能根除 LSCs，但矛盾的是，增加了 LSC 数量。CTL 分泌的 IFN-γ诱导 LSC 增殖和分化。只有在 CTL 分泌的 IFN-γ水平较低的情况下，效应 CTL 才能在白血病负荷较低的情况下消除 LSCs。此外，IFN-γ增加了来自 CML 患者的 CD34（+）干细胞/祖细胞的增殖和集落形成。我们的研究揭示了免疫系统促进白血病进展的新机制，这对于改善基于 T 细胞的白血病免疫疗法可能很重要。
