Inhibition of TGF-ß1 signaling restores NK cell anti-leukemia responses

Wang D, Sun Z, Zhu X, et al. GARP-Mediated Active TGF-ß1 Induces Bone Marrow NK Cell Dysfunction in AML Patients with Early Relapse Post-Allo-HSCT. Blood. 2022; (doi: 10.1182/blood.2022015474).

Researchers believe suppression of transforming growth factor ß1 (TGF-ß1) signaling might be one way to improve outcomes in patients with acute myeloid leukemia (AML) who relapse soon after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ex vivo investigations revealed that this AML patient subset suffers from impaired effector function of bone marrow-derived natural killer (BMNK) cells. Overexpression of glycoprotein A repetitions predominant (GARP) on the surface of CD4+ T cells trigger TGF-ß1 activation, resulting in elevated levels of TGF-ß1. Active TGF-ß1, in turn, inhibits mTORC1 activity, mitochondrial oxidative phosphorylation, proliferation, and cytotoxicity of BMNK cells. Pretreatment with galunisertib, which blocks this pathway, restored these anti-tumor functions in xenograft murine models. The study authors believe the approach may benefit not only AML patients recovering from allo-HSCT but also AML patients undergoing NK cell-based immunotherapy.

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Tags: AML, AlloHCT, patient care, T cells, Allo-HSCT, acute myeloid leukemia