Fu Denggang, Jiang Hua, Long Alan, Harris Ella, Guo Hongfen, Capitano Maegan L, Wrangle John, Faust Joshua R, Gopalakrishnapillai Anilkumar, Pasupuleti Santhosh Kumar, Ramdas Baskar, Kapur Reuben, Barwe Sonali P, Cheung Nai-Kong V, Paczesny Sophie
Department of Microbiology and Immunology and Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Nat Commun. 2025 Jul 14;16(1):6369. doi: 10.1038/s41467-025-61567-7.
Leukemia stem cells (LSCs) are a small yet powerful subset of leukemic cells that possess the ability to self-renew and have a long-term tumorigenic capacity, playing a crucial role in both leukemia development and therapy resistance. These LSCs are influenced by external and internal factors within the bone marrow niche. By delving into the intricate interplay between LSCs and their immune environment, we can pave the way for innovative immunotherapies that target both the malignant stem cells and the suppressive immune microenvironment, addressing both the "seed" and the "soil" simultaneously. Through the analysis of public datasets and patient samples, we show that elevated IL1RL1 expression correlates with poor prognosis and therapy resistance in acute myeloid leukemia (AML). At the core of this process, stem cell leukemogenesis initiation and maintenance signals are driven by a stress-induced IL-33/IL1RL1 autocrine loop. This LSC-induced IL-33/IL1RL1 signaling fosters an immune regulatory microenvironment. Therefore, IL1RL1 emerges as a promising therapeutic target, with IL1RL1-specific T cell-engaging bispecific antibodies holding great potential as cutting-edge immunotherapeutics for AML.
白血病干细胞（LSCs）是白血病细胞中一小部分但功能强大的亚群，具有自我更新能力和长期致瘤能力，在白血病发展和治疗耐药中起关键作用。这些LSCs受骨髓微环境中的外部和内部因素影响。通过深入研究LSCs与其免疫环境之间的复杂相互作用，我们可以为针对恶性干细胞和抑制性免疫微环境的创新免疫疗法铺平道路，同时解决“种子”和“土壤”问题。通过对公共数据集和患者样本的分析，我们发现IL1RL1表达升高与急性髓系白血病（AML）的不良预后和治疗耐药相关。在这个过程的核心，干细胞白血病发生起始和维持信号由应激诱导的IL-33/IL1RL1自分泌环驱动。这种LSC诱导产生的IL-33/IL1RL1信号促进了免疫调节微环境。因此，IL1RL1成为一个有前景的治疗靶点，具有IL1RL1特异性的T细胞接合双特异性抗体作为AML的前沿免疫疗法具有巨大潜力。
