Matte-Martone Catherine, Liu Jinling, Zhou Meng, Chikina Maria, Green Douglas R, Harty John T, Shlomchik Warren D
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
J Clin Invest. 2017 Jun 30;127(7):2765-2776. doi: 10.1172/JCI85736. Epub 2017 Jun 12.
The graft-versus-leukemia (GVL) effect in allogeneic hematopoietic stem cell transplantation (alloSCT) is potent against chronic phase chronic myelogenous leukemia (CP-CML), but blast crisis CML (BC-CML) and acute myeloid leukemias (AML) are GVL resistant. To understand GVL resistance, we studied GVL against mouse models of CP-CML, BC-CML, and AML generated by the transduction of mouse BM with fusion cDNAs derived from human leukemias. Prior work has shown that CD4+ T cell-mediated GVL against CP-CML and BC-CML required intact leukemia MHCII; however, stem cells from both leukemias were MHCII negative. Here, we show that CP-CML, BC-CML, and AML stem cells upregulate MHCII in alloSCT recipients. Using gene-deficient leukemias, we determined that BC-CML and AML MHC upregulation required IFN-γ stimulation, whereas CP-CML MHC upregulation was independent of both the IFN-γ receptor (IFN-γR) and the IFN-α/β receptor IFNAR1. Importantly, IFN-γR-deficient BC-CML and AML were completely resistant to CD4- and CD8-mediated GVL, whereas IFN-γR/IFNAR1 double-deficient CP-CML was fully GVL sensitive. Mouse AML and BC-CML stem cells were MHCI+ without IFN-γ stimulation, suggesting that IFN-γ sensitizes these leukemias to T cell killing by mechanisms other than MHC upregulation. Our studies identify the requirement of IFN-γ stimulation as a mechanism for BC-CML and AML GVL resistance, whereas independence from IFN-γ renders CP-CML more GVL sensitive, even with a lower-level alloimmune response.
异基因造血干细胞移植（alloSCT）中的移植物抗白血病（GVL）效应对慢性期慢性髓性白血病（CP-CML）有强大作用，但急变期CML（BC-CML）和急性髓系白血病（AML）具有GVL抗性。为了解GVL抗性，我们研究了GVL对通过用源自人类白血病的融合cDNA转导小鼠骨髓产生的CP-CML、BC-CML和AML小鼠模型的作用。先前的研究表明，CD4 + T细胞介导的针对CP-CML和BC-CML的GVL需要完整的白血病MHCII；然而，这两种白血病的干细胞均为MHCII阴性。在此，我们表明CP-CML、BC-CML和AML干细胞在alloSCT受者中上调MHCII。使用基因缺陷型白血病，我们确定BC-CML和AML的MHC上调需要IFN-γ刺激，而CP-CML的MHC上调独立于IFN-γ受体（IFN-γR）和IFN-α/β受体IFNAR1。重要的是，IFN-γR缺陷型BC-CML和AML对CD4和CD8介导的GVL完全抗性，而IFN-γR/IFNAR1双缺陷型CP-CML对GVL完全敏感。小鼠AML和BC-CML干细胞在没有IFN-γ刺激的情况下为MHCI +，这表明IFN-γ通过MHC上调以外的机制使这些白血病对T细胞杀伤敏感。我们的研究确定IFN-γ刺激的需求是BC-CML和AML GVL抗性的一种机制，而独立于IFN-γ使CP-CML对GVL更敏感，即使同种异体免疫反应水平较低也如此。
