Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.
Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
Clin Cancer Res. 2022 Jul 15;28(14):3141-3155. doi: 10.1158/1078-0432.CCR-21-3594.
The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Treg) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFNγ released by AML cells in BM Treg induction and its impact on AML prognosis.
BM aspirates from patients with AML were subdivided according to IFNG expression. Gene expression profiles in INFγhigh and IFNγlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFNγ release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell cocultures. In mice, AML cells silenced for ifng expression were injected intrabone.
IFNγhigh AML samples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. In contrast, in patients with AML, high IFNG expression was associated with poor overall survival. Notably, IFNγ release by AML cells positively correlated with a higher BM suppressive Treg frequency. In coculture experiments, IFNγhigh AML cells modified MSC transcriptome by upregulating IFNγ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFNγ release by AML cells on MSC-derived Treg induction. In vivo, the genetic ablation of IFNγ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment.
IFNγ release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunologic landscape toward Treg induction, contributing to an immunotolerant microenvironment. See related commentary by Ferrell and Kordasti, p. 2986.
骨髓基质和免疫（stromal and immune bone marrow，BM）微环境正成为急性髓系白血病（acute myeloid leukemia，AML）的关键决定因素。调节性 T 细胞（regulatory T cells，Treg）在 AML 微环境中富集，但潜在机制仍未得到充分阐明。在这里，我们研究了 AML 细胞释放的 IFNγ在 BM Treg 诱导中的作用及其对 AML 预后的影响。
根据 IFNG 表达情况将 AML 患者的 BM 抽吸物进行细分。通过微阵列和 NanoString 分析比较 INFγ高和 IFNγ低样本中的基因表达谱，并用于计算预后指数。在间充质基质细胞（mesenchymal stromal cell，MSC）/AML 细胞共培养物中研究 IFNγ对 BM 微环境的释放效应。在小鼠中，将沉默 ifng 表达的 AML 细胞注入骨髓内。
IFNγ高 AML 样本显示炎症基因上调，通常与癌症的良好预后相关。相比之下，在 AML 患者中，高 IFNG 表达与总体生存不良相关。值得注意的是，AML 细胞释放的 IFNγ与更高的 BM 抑制性 Treg 频率呈正相关。在共培养实验中，IFNγ高 AML 细胞通过上调与 Treg 诱导相关的 IFNγ依赖性基因，如吲哚胺 2,3-双加氧酶 1（indoleamine 2,3-dioxygenase 1，IDO1），改变 MSC 转录组。IDO1 抑制剂阻断了 AML 细胞释放 IFNγ对 MSC 衍生 Treg 诱导的影响。在体内，AML 细胞 IFNγ 产生的基因缺失减少了 MSC IDO1 表达和 Treg 浸润，阻碍了 AML 植入。
AML 细胞释放的 IFNγ在 MSC 中诱导免疫调节程序，并重塑 BM 免疫景观，促进 Treg 诱导，有助于形成免疫耐受微环境。请参阅相关评论文章，Kordasti 等人，第 2986 页。
