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

• Published in: Cell reports. Medicine 2024-11, Vol.5 (11), p.101826, Article 101826
• Main Authors: Rubino, Viviana, Hüppi, Michelle, Höpner, Sabine, Tortola, Luigi, Schnüriger, Noah, Legenne, Hugo, Taylor, Lea, Voggensperger, Svenja, Keller, Irene, Bruggman, Remy, Kronig, Marie-Noëlle, Bacher, Ulrike, Kopf, Manfred, Ochsenbein, Adrian F., Riether, Carsten
• Format: Article
• Language: English
• Subjects: AML; Animals; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD70-targeting CAR T cells; Cell Differentiation - drug effects; Cell Line, Tumor; cytarabine; Cytarabine - pharmacology; Cytarabine - therapeutic use; Female; Humans; IL-21; Immunotherapy, Adoptive - methods; Interleukins - metabolism; leukemia stem cell; 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; p38 MAPK; Receptors, Interleukin-21 - genetics; Receptors, Interleukin-21 - metabolism; self-renewal; Signal Transduction - drug effects; stemness; Xenograft Model Antitumor Assays
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101826

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. [Display omitted] •CD4+ T cell-derived IL-21 reduces stemness and promotes the differentiation of AML LSCs•IL-21 reduces LSC function by activating ROS and p38-MAPK signaling•Low-dose IL-21 treatment prolongs the survival of MLL-AF9 and PDX AML mice•IL-21 treatment synergized with ARA-C and CAR T cell treatment Rubino et al. show that CD4+ T cell-derived IL-21 promotes LSC differentiation by activating MAPK signaling and that IL-21 treatment synergistically reduces LSCs in combination with chemotherapy and CAR T cell treatment. These results provide a rationale for the use of IL-21 in the treatment of patients with AML.