Human ILC1s Target Leukemia Stem Cells and Control Development of AML

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.886-886
• Main Authors: Li, Zhenlong, Tang, Hejun, Chen, Victoria, Ma, Rui, Zhang, Jianying, Marcucci, Guido, Yu, Jianhua, Caligiuri, Michael A
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-190767

Acute myeloid leukemia (AML) is a devastating disease with a median 5-year survival of only 40-45% for patients younger than age 65 who are treated with standard chemotherapy. Although in some cases allogeneic stem cell transplantation has proven to be curative, the treatment-related mortality and the risk for disease relapse due to persistence of leukemia stem cells (LSCs) remains relatively high. Therefore, safer and more effective novel therapeutic approaches are needed to improve the clinical outcomes of patients with AML. Innate lymphoid cell (ILC) is critical in mediating immune responses and regulating tissue homeostasis and inflammation. We recently reported that mouse ILC1s contribute to the control of AML by eliminating LSCs and inhibiting their differentiation into myeloid blasts, and functional impairment of mouse ILC1s in AML leads to the outgrowth of LSCs and disease relapse (Li et al., Nature Immunology. 2022). However, the full role and mechanistic characterization of human ILC1s in anti-tumor responses to AML remains to be fully explored. Upon analysis of ILC1s in the blood of patients with AML at the onset of disease, we observed a highly significant reduction in the total ILC1s count among lineage-negative cells (Lin −, defined asdepletion of CD3, CD4, CD8, CD14, CD15, CD16, CD19, CD20, CD33, CD34, CD203c, FceRI, and CD56 positive cells) relative to healthy donors ( p = 0.031, n = 6 healthy donors; n = 4 patients with AML). Further, functional ILC1s positive for IFNγ and DNAM-1 were significantly reduced in the patients with AML compared to healthy donors. Analysis of 106 AML cases from the Cancer Genome Atlas (TCGA) showed that AML patients with a high ILC1 gene signature had a significantly prolonged overall survival compared to AML patients with a low ILC1 gene signature. By directly interacting with LSCs, human ILC1s can eliminate LSCs via the production of IFNγ. Through Wright-Giemsa staining, we observed that ILC1s blocked the differentiation of CD34 +CD38 − cells into macrophage-like leukemia-supporting cells, which were previously reported to support the growth of leukemic cells rather than inhibit them. Flow cytometry of these differentiated cells showed that some exhibited the tumor-promoting phenotype with expression of CD11b and CD206. These macrophage-like leukemia-supporting cells significantly decreased when co-cultured with ILC1s. This differentiation is at least partially dependent on TNF secreted by ILC1s. We also perfo