An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells.
An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells.
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DOI：
10.1371/journal.pone.0144594
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hosen N
中科院分区：
文献类型：
--
作者：
Hasegawa K;Tanaka S;Fujiki F;Morimoto S;Nakajima H;Tatsumi N;Nakata J;Takashima S;Nishida S;Tsuboi A;Oka Y;Oji Y;Kumanogoh A;Sugiyama H;Hosen N
白血病的基质环境与局部进展为实体瘤的肿瘤有很大不同，免疫监视在白血病中的生理重要性尚不清楚。然而，目前可用的小鼠白血病模型在分析白血病发展的免疫调节的背景下具有关键的局限性。在这项研究中，我们将小鼠MLL/AF 9白血病起始细胞转移到免疫活性受体小鼠中，而无需任何预处理，如辐射，然后分析自发T细胞对白血病细胞中表达的免疫原性抗原的应答。当转移最少数量的白血病起始细胞用于移植时，大多数（如果不是全部）野生型小鼠的适应性免疫反应会根除白血病细胞，但Rag 2-/-受体小鼠则不然，因为它们缺乏适应性免疫。相比之下，移植了大量白血病细胞的小鼠总是发生白血病。在晚期白血病小鼠中，抗原特异性CTL也扩增，但对抗原刺激无反应，并表达高水平的PD-1和LAG-3。这些结果提供了第一个明确的证明，自发的CTL反应的肿瘤细胞抗原有可能根除白血病，而抗原特异性的CTL是耗尽在晚期白血病的动物。这种免疫活性小鼠白血病模型为开发有效的白血病免疫疗法提供了一个有用的平台。
Leukemia differs substantially with respect to stromal milieu from tumors that progress locally as solid masses, and the physiological importance of immunosurveillance in leukemia remains unclear. However, currently available mouse leukemia models have critical limitations in the context of analyzing immunological regulation of leukemia development. In this study, we transferred mouse MLL/AF9 leukemia-initiating cells into immunocompetent recipient mice without any pre-conditioning such as irradiation, and then analyzed the spontaneous T cell response to an immunogenic antigen expressed in leukemia cells. When the minimum numbers of leukemia-initiating cells for engraftment were transferred, leukemia cells were eradicated by the adaptive immune response in most, if not all, wild-type mice, but not in Rag2 -/- recipient mice, which lack adaptive immunity. By contrast, mice transplanted with larger numbers of leukemia cells always developed leukemia. In mice with advanced leukemia, antigen-specific CTLs were also expanded, but were unresponsive to antigen stimulation and expressed high levels of PD-1 and LAG-3. These results provide the first clear demonstration that the spontaneous CTL response to a tumor-cell antigen has the potential to eradicate leukemia, whereas antigen-specific CTLs are exhausted in animals with advanced leukemia. This immunocompetent mouse leukemia model provides a useful platform for developing effective immunotherapies against leukemia.