GARP-mediated active TGF-β1 induces bone marrow NK cell dysfunction in AML patients with early relapse post–allo-HSCT

• Published in: Blood 2022-12, Vol.140 (26), p.2788-2804
• Main Authors: Wang, Dongyao, Sun, Zimin, Zhu, Xiaoyu, Zheng, Xiaohu, Zhou, Yonggang, Lu, Yichen, Yan, Peidong, Wang, Huiru, Liu, Huilan, Jin, Jing, Zhu, Huaiping, Sun, Rui, Wang, Yi, Fu, Binqing, Tian, Zhigang, Wei, Haiming
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow - pathology; Chronic Disease; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Killer Cells, Natural - pathology; Leukemia, Myeloid, Acute - pathology; Mice; Recurrence; Transforming Growth Factor beta1; Transplantation, Homologous
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2022015474

•GARP-induced activation of TGF-β1 attenuates effector functions of BMNK cells ex vivo.•Pharmacologic inhibition of TGF-β1 signaling restores NK cell−mediated antileukemic responses in leukemia xenograft mouse models. [Display omitted] Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow−derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor β1 (TGF-β1) were associated with impaired effector function of BMNK cells in these AML patients. TGF-β1 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-β1 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-β1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-β1 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-β1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell−based immunotherapy. Natural killer (NK) cells reconstitute early after allogeneic stem cell transplants and are associated with protection against acute myeloid leukemia (AML) relapse. Wang and colleagues reveal that in patient samples, glycoprotein A repetitions predominant (GARP) molecules present on CD4+ regulatory T cells activate latent TGF-β1 to downregulate NK cell-effector functions in patients, enabling early AML relapse. The authors report that TGF-β1 inhibitors restore the antileukemia effector functions of NK cells in xenografts, potentially pointing to how NK cell-mediated control of AML can be increased in patients.