IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy

Viviana Rubino; Michelle Hüppi; Sabine Höpner; Luigi Tortola; Noah Schnüriger; Hugo Legenne; Lea Taylor; Svenja Voggensperger; Irene Keller; Remy Bruggman; Marie-Noëlle Kronig; Ulrike Bacher; Manfred Kopf; Adrian F Ochsenbein; Carsten Riether

doi:10.1016/j.xcrm.2024.101826

IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy

Cell Rep Med. 2024 Nov 19;5(11):101826. doi: 10.1016/j.xcrm.2024.101826. Epub 2024 Nov 12.

Authors

Affiliations

¹ Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
² Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
³ Institute for Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
⁴ Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland.
⁵ Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁶ Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁷ Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. Electronic address: carsten.riether@insel.ch.

Abstract

Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4⁺ T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML.

Keywords: AML; CD70-targeting CAR T cells; IL-21; cytarabine; leukemia stem cell; p38 MAPK; self-renewal; stemness.

MeSH terms

Animals
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Cell Differentiation / drug effects
Cell Line, Tumor
Cytarabine* / pharmacology
Cytarabine* / therapeutic use
Female
Humans
Immunotherapy, Adoptive / methods
Interleukin-21
Interleukins* / metabolism
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / metabolism
Leukemia, Myeloid, Acute* / pathology
Leukemia, Myeloid, Acute* / therapy
Male
Mice
Mice, Inbred C57BL
Neoplastic Stem Cells* / drug effects
Neoplastic Stem Cells* / metabolism
Neoplastic Stem Cells* / pathology
Receptors, Interleukin-21 / genetics
Receptors, Interleukin-21 / metabolism
Signal Transduction* / drug effects
Xenograft Model Antitumor Assays

Substances

Interleukin-21
Cytarabine
Interleukins
Receptors, Interleukin-21