Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation

Abstract

Haploidentical stem cell transplantation (haplo-SCT) achieves superior or at least comparable clinical outcomes to HLA-matched sibling donor transplantation (MSDT) in treating hematological malignancies. To define the underlying regulatory dynamics, we analyzed time courses of leukemia burden and immune abundance of haplo-SCT or MSDT from multiple dimension. First, we employed two nonirradiated leukemia mouse models which carried human AML-ETO or MLL-AF9 fusion gene to establish haplo-identical and major histocompatibility (MHC)-matched transplantation models and investigated the immune cell dynamic response during leukemia development in vivo. We found that haplo-matching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mice survival and reduced leukemia burden. The stronger graft-versus-leukemia activity in haplo-SCT group mainly induced by decreased apoptosis and increased cytotoxic cytokine secretion including tumor necrosis factor–α, interferon-γ, pore-forming proteins and CD107a secreted by T cells or natural killer cells. Furthermore, we conducted a prospective clinical trial which enrolled 135 patients with t(8;21) acute myeloid leukemia that displayed minimal residual disease before transplantation and underwent either haplo-SCT or MSDT. The results showed that the haplo-SCT slowed the kinetics of the leukemia burden in vivo and reduced the cumulative incidence of relapse compared with MSDT. Ex vivo experiments showed that, 1 year after transplantation, cytotoxic T lymphocytes from the haplo-SCT group had higher cytotoxicity than those from the MSDT group during the same period. Our results unraveled the role of immune cells in superior antileukemia effects of haplo-SCT compared with MSDT.

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Acknowledgements

This work was partly supported by grants from the National Key Research and Development Program of China (2017YFA0104500), the Beijing Municipal Science and Technology Commission (Z181100009618032), the National Natural Science Foundation of China (Grant No. 81621001, 81530046, 81770189, 81670186, 81870141 and 82070185), CAMS Innovation Fund for Medical Sciences (CIFMS) (grant number: 2019-I2M-5-034) and the Peking University Clinical Scientist Program (BMU2019LCKXJ003). We thank all of the faculty members who participated in these studies.

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Contributions: X.-J.H. designed the study; X.-J.H., Y.-J.C., and H.-D. G. conceived the project and drafted the manuscript; H.-D. G. and Y. H. performed the in vivo mouse models experiments and ex vivo experiments; Y.-J.C. analyzed the clinical data; all authors contributed to data interpretation and manuscript preparation. All authors approved the final version of the manuscript.

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Correspondence to Xiao-Jun Huang.

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Guo, H., Chang, YJ., Hong, Y. et al. Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation. Cell Mol Immunol (2021). https://doi.org/10.1038/s41423-020-00597-1

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Keywords

  • Graft-versus-leukemia
  • Haplo-SCT
  • MSDT
  • AML
  • MRD

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