Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2 , LAG3 , TIGIT , and CTLA4 . BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.

中文翻译：

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BATF 是 AML 中 NK 细胞表观遗传重编程和功能障碍的主要驱动因素


骨髓增生异常综合征和急性髓系白血病 （AML） 属于髓系恶性肿瘤的连续疾病谱，在复发/难治性情况下预后不良，需要新的疗法。来自髓系恶性肿瘤患者的自然杀伤 （NK） 细胞在单细胞转录组学和蛋白质组学水平上表现出整体功能障碍，杀伤能力受损、代谢改变以及表型耗竭。在这项研究中，我们发现这种功能障碍是通过 NK 细胞和髓系原始细胞之间的串扰介导的，因此需要细胞间接触。NK 细胞功能障碍可以通过靶向 αvβ-整合素/TGF-β/SMAD 通路来预防，但一旦建立，由于深刻的表观遗传重编程，它就会持续存在。我们确定 BATF 是 AML 中 NK 细胞功能障碍的核心转录因子和主要介质。从机制上讲，我们发现 BATF 受 SMAD2/3 直接调节和诱导，进而与与 NK 细胞耗竭相关的关键基因结合，例如 HAVCR2 、 LAG3 、 TIGIT 和 CTLA4 。BATF 缺失增强了 NK 细胞在体外和体内对抗 AML 的功能。总的来说，我们的研究结果揭示了 AML 中 NK 免疫逃避的先前未确定的机制，表现为髓系原始细胞对 NK 细胞的表观遗传重新布线和失活。这项工作强调了使用健康的同种异体 NK 细胞作为过继细胞疗法治疗髓系恶性肿瘤患者的重要性，并结合了旨在通过靶向 TGF-β 通路或 BATF 预防功能障碍的策略。