Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway Journal Article
| Authors: | Fu, D.; Jiang, H.; Long, A.; Harris, E.; Guo, H.; Capitano, M. L.; Wrangle, J.; Faust, J. R.; Gopalakrishnapillai, A.; Pasupuleti, S. K.; Ramdas, B.; Kapur, R.; Barwe, S. P.; Cheung, N. K. V.; Paczesny, S. |
| Article Title: | Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway |
| Abstract: | 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. © The Author(s) 2025. |
| Keywords: | signal transduction; adult; clinical article; controlled study; human cell; genetics; leukemia, myeloid, acute; nonhuman; comparative study; flow cytometry; cancer diagnosis; cd3 antigen; cd8 antigen; animal cell; mouse; animal; metabolism; animals; mice; immune system; signaling; animal experiment; tumor xenograft; drug effect; pathology; cell line, tumor; immunology; correlation analysis; immune response; immunotherapy; gamma interferon; neoplastic stem cells; leukemia cell; leukemogenesis; tumor cell line; cancer stem cell; bone; therapy resistance; oxidative stress; immunity; kaplan meier method; tumor; drug therapy; immunocompetent cell; tumor microenvironment; demographics; acute myeloid leukemia; procedures; body weight loss; cancer prognosis; bispecific antibody; interleukin 33; cell component; humans; human; male; female; article; interleukin-33; bone marrow aspiration; interleukin 1 receptor like 1 protein; interleukin-1 receptor-like 1 protein; il1rl1 protein, human; il33 protein, human |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-07-14 |
| Start Page: | 6369 |
| Language: | English |
| DOI: | 10.1038/s41467-025-61567-7 |
| PUBMED: | 40659660 |
| PROVIDER: | scopus |
| PMCID: | PMC12259856 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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