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Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease

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Abstract

Although glucorticosteroids (GCs) are the standard first-line therapy for acute graft-versus-host disease (aGvHD), nearly 50% of aGvHD patients have no response to GCs. The role of T cell metabolism in murine aGvHD was recently reported. However, whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate aGvHD remains to be elucidated. Increased glycolysis, characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and higher rates of glucose consumption and lactate production were found in T cells from aGvHD patients. Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells. In a humanized mouse model, PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented aGvHD, respectively. Importantly, our integrated data from patient samples in vitro, in a humanized xenogeneic murine model of aGvHD and graft-versus-leukaemia (GVL) demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate aGvHD without loss of GVL effects. Together, the current study indicated that glycolysis is critical for T cell activation and induction of human aGvHD. Therefore, the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for aGvHD patients. GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for aGvHD patients.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2021YFA1100904, 2019YFC0840606 & 2017YFA0104500), the National Natural Science Foundation of China (82070188, 81930004 & 82100227) and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81621001). The authors thank all of the core facilities at the Peking University Institute of Hematology for patient care and sample collection. American Journal Experts (www.journalexperts.com) provided editorial assistance to the authors during the preparation of the manuscript.

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  1. Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China

    Qi Wen, Zheng-Li Xu, Yu Wang, Meng Lv, Yang Song, Zhong-Shi Lyv, Tong Xing, Lan-Ping Xu, Xiao-Hui Zhang, Xiao-Jun Huang & Yuan Kong

  2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100044, China

    Yang Song, Zhong-Shi Lyv & Xiao-Jun Huang

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  1. Qi Wen
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Wen, Q., Xu, ZL., Wang, Y. et al. Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease. Sci. China Life Sci. 66, 528–544 (2023). https://doi.org/10.1007/s11427-022-2170-2

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