Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Cellular & Molecular Immunology volume 18, pages 1172–1185 (2021)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Appelbaum, F. R. Hematopoietic-cell transplantation at 50. N. Engl. J. Med. 357, 1472–1475 (2007).

    CAS  PubMed  Google Scholar 

  2. Dohner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129, 424–447 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. Wang, Y. et al. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood 125, 3956–3962 (2015).

    CAS  PubMed  Google Scholar 

  4. Koreth, J. et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301, 2349–2361 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Cornelissen, J. J. et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 109, 3658–3666 (2007).

    CAS  PubMed  Google Scholar 

  6. Horowitz, M. M. et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75, 555–562 (1990).

    CAS  PubMed  Google Scholar 

  7. Lamers, C. H. et al. CD4+ T-cell alloreactivity toward mismatched HLA class II alleles early after double umbilical cord blood transplantation. Blood 128, 2165–2174 (2016).

    CAS  PubMed  Google Scholar 

  8. Matte-Martone, C. et al. Differential requirements for myeloid leukemia IFN-gamma conditioning determine graft-versus-leukemia resistance and sensitivity. J. Clin. Invest. 127, 2765–2776 (2017).

    PubMed  PubMed Central  Google Scholar 

  9. Chang, Y. J. et al. Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry: a retrospective and prospective analysis. J. Hematol. Oncol. 10, 134 (2017).

    PubMed  PubMed Central  Google Scholar 

  10. Chang, Y. J. et al. Haploidentical donor is preferred over matched sibling donor for pre-transplantation MRD positive ALL: a phase 3 genetically randomized study. J. Hematol. Oncol. 13, 27 (2020).

    PubMed  PubMed Central  Google Scholar 

  11. Yu, S. et al. Haploidentical transplantation might have superior graft-versus-leukemia effect than HLA-matched sibling transplantation for high-risk acute myeloid leukemia in first complete remission: a prospective multicentre cohort study. Leukemia, https://doi.org/10.1038/s41375-019-0686-3 (2019).

  12. Barnes, D. W. & Loutit, J. F. Treatment of murine leukaemia with x-rays and homologous bone marrow. Ii. Br. J. Haematol. 3, 241–252 (1957).

    CAS  PubMed  Google Scholar 

  13. Schroeder, M. A. & DiPersio, J. F. Mouse models of graft-versus-host disease: advances and limitations. Dis. Model Mech. 4, 318–333 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Reddy, P., Negrin, R. & Hill, G. R. Mouse models of bone marrow transplantation. Biol. Blood Marrow Transpl. 14, 129–135 (2008).

    Google Scholar 

  15. Wang, Y. Y. et al. C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice. Proc. Natl Acad. Sci. USA 108, 2450–2455 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Guo, H. et al. PBX3 is essential for leukemia stem cell maintenance in MLL-rearranged leukemia. Int. J. Cancer 141, 324–335 (2017).

    CAS  PubMed  Google Scholar 

  17. Balsat, M. et al. Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the acute leukemia French Association Group. J. Clin. Oncol. 35, 185–193 (2017).

    CAS  PubMed  Google Scholar 

  18. Zhu, H. H. et al. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood 121, 4056–4062 (2013).

    CAS  PubMed  Google Scholar 

  19. Xu, L. et al. The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology. J. Hematol. Oncol. 11, 33 (2018).

    PubMed  PubMed Central  Google Scholar 

  20. Wang, Y. et al. In adults with t(8;21)AML, posttransplant RUNX1/RUNX1T1-based MRD monitoring, rather than c-KIT mutations, allows further risk stratification. Blood 124, 1880–1886 (2014).

    CAS  PubMed  Google Scholar 

  21. Ravandi, F., Walter, R. B. & Freeman, S. D. Evaluating measurable residual disease in acute myeloid leukemia. Blood Adv. 2, 1356–1366 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Thepot, S. et al. The graft-versus-leukemia effect is mainly restricted to NIH-defined chronic graft-versus-host disease after reduced intensity conditioning before allogeneic stem cell transplantation. Leukemia 24, 1852–1858 (2010).

    CAS  PubMed  Google Scholar 

  23. Blom, S. et al. Systems pathology by multiplexed immunohistochemistry and whole-slide digital image analysis. Sci. Rep. 7, 15580 (2017).

    PubMed  PubMed Central  Google Scholar 

  24. Bruck, O. et al. Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML. Leukemia 32, 1643–1656 (2018).

    CAS  PubMed  Google Scholar 

  25. Wang, Y. et al. Haploidentical versus matched-sibling transplant in adults with philadelphia-negative high-risk acute lymphoblastic leukemia: a biologically phase III randomized study. Clin. Cancer Res. 22, 3467–3476 (2016).

    CAS  PubMed  Google Scholar 

  26. Yan, C. H. et al. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 119, 3256–3262 (2012).

    CAS  PubMed  Google Scholar 

  27. Chang, Y. J. et al. Controlled, randomized, open-label trial of risk-stratified corticosteroid prevention of acute graft-versus-host disease after haploidentical transplantation. J. Clin. Oncol. 34, 1855–1863 (2016).

    CAS  PubMed  Google Scholar 

  28. Gauthier, J. et al. Better outcome with haploidentical over HLA-matched related donors in patients with Hodgkin’s lymphoma undergoing allogeneic haematopoietic cell transplantation-a study by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy. Bone Marrow Transpl. 53, 400–409 (2018).

    CAS  Google Scholar 

  29. Mariotti, J. et al. T cell-replete haploidentical transplantation with post-transplantation cyclophosphamide for Hodgkin Lymphoma relapsed after autologous transplantation: reduced incidence of relapse and of chronic graft-versus-host disease compared with HLA-identical related donors. Biol. Blood Marrow Transpl. 24, 627–632 (2018).

    CAS  Google Scholar 

  30. Srour, S. A. et al. Haploidentical transplantation for acute myeloid leukemia patients with minimal/measurable residual disease at transplantation. Am. J. Hematol. 94, 1382–1387 (2019).

    CAS  PubMed  Google Scholar 

  31. Wang, Y. et al. Superior graft-versus-leukemia effect associated with transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute leukemia: an historic comparison. Biol. Blood Marrow Transpl. 17, 821–830 (2011).

    Google Scholar 

  32. Zhang, Y. & Zhang, Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol. Immunol. 17, 807–821 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Mercier, F. E., Ragu, C. & Scadden, D. T. The bone marrow at the crossroads of blood and immunity. Nat. Rev. Immunol. 12, 49–60 (2011).

    PubMed  PubMed Central  Google Scholar 

  34. Davidson-Moncada, J., Viboch, E., Church, S. E., Warren, S. E. & Rutella, S. Dissecting the Immune Landscape of Acute Myeloid Leukemia. Biomedicines 6, https://doi.org/10.3390/biomedicines6040110 (2018).

  35. Spitzer, M. H. et al. Immunology. An interactive reference framework for modeling a dynamic immune system. Science 349, 1259425 (2015).

    PubMed  PubMed Central  Google Scholar 

  36. Bonnet, D., Warren, E. H., Greenberg, P. D., Dick, J. E. & Riddell, S. R. CD8(+) minor histocompatibility antigen-specific cytotoxic T lymphocyte clones eliminate human acute myeloid leukemia stem cells. Proc. Natl Acad. Sci. USA 96, 8639–8644 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Rees, R. C. MHC restricted and non-restricted killer lymphocytes. Blood Rev. 4, 204–210 (1990).

    CAS  PubMed  Google Scholar 

  38. Inamoto, Y. et al. Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups. Haematologica 101, 1592–1602 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wakamatsu, M. et al. Impacts of thymoglobulin in patients with acute leukemia in remission undergoing allogeneic HSCT from different donors. Blood Adv. 3, 105–115 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kroger, N. et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N. Engl. J. Med. 374, 43–53 (2016).

    PubMed  Google Scholar 

  41. Arai, Y. et al. Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy. Blood 126, 415–422 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Breithaupt, H. et al. Clinical results and pharmacokinetics of high-dose cytosine arabinoside (HD ARA-C). Cancer 50, 1248–1257 (1982).

    CAS  PubMed  Google Scholar 

  43. Chang, Y. J., Zhao, X. Y. & Huang, X. J. Immune reconstitution after haploidentical hematopoietic stem cell transplantation. Biol. Blood Marrow Transpl. 20, 440–449 (2014).

    CAS  Google Scholar 

  44. Hu, L. J. et al. NK cell reconstitution following unmanipulated HLA-mismatched/haploidentical transplantation compared with matched sibling transplantation. Sci. China Life Sci. 63, 781–784 (2020).

    PubMed  Google Scholar 

Download references

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.

Author information

Author notes

  1. These authors contributed equally: Hui-Dong Guo, Ying-Jun Chang, Yan Hong

Authors and Affiliations

  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, No. 11 South Street of Xizhimen, Xicheng District, 100044, Beijing, China

    Huidong Guo, Ying-Jun Chang, Yan Hong, Lan-Ping Xu, Yu Wang, Xiao-Hui Zhang, Ming Wang, Huan Chen, Yu-Hong Chen, Feng-Rong Wang,  Wei-Han, Yu-Qian Sun, Chen-Hua Yan, Fei-Fei Tang, Xiao-Dong Mo, Kai-Yan Liu & Xiao-Jun Huang

  2. Peking-Tsinghua Center for Life Sciences, 100871, Beijing, China

    Xiao-Jun Huang

  3. Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, China

    Xiao-Jun Huang

Authors
  1. Huidong Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying-Jun Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lan-Ping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiao-Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu-Hong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Feng-Rong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei-Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yu-Qian Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Chen-Hua Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fei-Fei Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xiao-Dong Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kai-Yan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Xiao-Jun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Xiao-Jun Huang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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 18, 1172–1185 (2021). https://doi.org/10.1038/s41423-020-00597-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-00597-1

Keywords

This article is cited by

Search

Advanced search

Quick links