SpringerLink
Log in

CD277 agonist enhances the immunogenicity of relapsed/refractory acute myeloid leukemia towards Vδ2+ T cell cytotoxicity

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Relapse and refractoriness remain the major obstacles in clinical treatment of acute myeloid leukemia (AML). Efficacy of current therapeutic strategies for relapsed/refractory (R/R) AML is generally unsatisfying. Vδ2+ T cells have become an attractive candidate for immunotherapy of various types of tumors. However, the results were not exciting in some pilot studies utilizing Vδ2 cell-based protocols to treat R/R AML. Functional receptors on Vδ2 cells and immunogenic ligands on leukemia cells are both critical to the anti-AML effect of Vδ2 cells, which have not been characterized in the context of R/R AML. CD277 can bind to phosphoantigens and promote the activation of Vδ2 cells. Anti-CD277 (clone 20.1) monoclonal antibody (20.1 mAb) has been identified as an agonist of CD277. Whether 20.1 mAb sensitizes R/R AML cells awaits investigation. Herein, we showed that the expressions of activating receptors on Vδ2 cells and CD277 on leukemia cells were deficient in patients with R/R AML. While agonists for NKG2D and TRAIL ligands did not increase the immunogenicity of R/R AML cells, 20.1 mAb significantly enhanced the cytotoxicity of Vδ2 cells on the drug-resistant human AML cell line and different types of primary AML cells from R/R patients. The sensitizing effect of 20.1 mAb was dependent on inducing degranulation of Vδ2 cells. These findings suggest a decisive role of CD277 in mediating the recognition of R/R AML cells by Vδ2+ T cells. CD277 agonist combining adoptive transfer of Vδ2+ T cells may improve the efficacy in the treatment of R/R AML.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Pollyea DA, Bixby D, Perl A et al (2021) NCCN guidelines insights: acute myeloid leukemia, version 2.2021. J Natl Compr Canc Netw 19(1):16–27. https://doi.org/10.6004/jnccn.2021.0002

    Article  PubMed  Google Scholar 

  2. Thol F, Ganser A (2020) Treatment of relapsed acute myeloid leukemia. Curr Treat Options Oncol 21(8):66. https://doi.org/10.1007/s11864-020-00765-5

    Article  PubMed  PubMed Central  Google Scholar 

  3. Döhner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 373(12):1136–1152. https://doi.org/10.1056/NEJMra1406184

    Article  CAS  PubMed  Google Scholar 

  4. Rashidi A, Weisdorf DJ, Bejanyan N (2018) Treatment of relapsed/refractory acute myeloid leukaemia in adults. Br J Haematol 181(1):27–37. https://doi.org/10.1111/bjh.15077

    Article  PubMed  Google Scholar 

  5. Heinicke T, Krahl R, Kahl C et al (2021) Allogeneic hematopoietic stem cell transplantation improves long-term outcome for relapsed AML patients across all ages: results from two East German Study Group Hematology and Oncology (OSHO) trials. Ann Hematol 100(9):2387–2398. https://doi.org/10.1007/s00277-021-04565-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gertner-Dardenne J, Castellano R, Mamessier E et al (2012) Human Vγ9Vδ2 T cells specifically recognize and kill acute myeloid leukemic blasts. J Immunol 188(9):4701–4708. https://doi.org/10.4049/jimmunol.1103710

    Article  CAS  PubMed  Google Scholar 

  7. Barros MS, de Araújo ND, Magalhães-Gama F et al (2021) γδ T cells for leukemia immunotherapy: new and expanding trends. Front Immunol 12:729085. https://doi.org/10.3389/fimmu.2021.729085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yazdanifar M, Barbarito G, Bertaina A et al (2020) γδ T cells: the ideal tool for cancer immunotherapy. Cells 9(5). https://doi.org/10.3390/cells9051305

  9. Gao H, Liu R, Wu N et al (2020) Valproic acid enhances pamidronate-sensitized cytotoxicity of Vδ2(+) T cells against EBV-related lymphoproliferative cells. Int Immunopharmacol 88:106890. https://doi.org/10.1016/j.intimp.2020.106890

    Article  CAS  PubMed  Google Scholar 

  10. Déchanet-Merville J, Prinz I (2020) From basic research to clinical application of γδ T cells. Immunol Rev 298(1):5–9. https://doi.org/10.1111/imr.12931

    Article  CAS  PubMed  Google Scholar 

  11. Kunzmann V, Smetak M, Kimmel B et al (2012) Tumor-promoting versus tumor-antagonizing roles of gammadelta T cells in cancer immunotherapy: results from a prospective phase I/II trial. J Immunother 35(2):205–213. https://doi.org/10.1097/CJI.0b013e318245bb1e

    Article  CAS  PubMed  Google Scholar 

  12. Sandstrom A, Peigné CM, Léger A et al (2014) The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells. Immunity 40(4):490–500. https://doi.org/10.1016/j.immuni.2014.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang H, Henry O, Distefano MD et al (2013) Butyrophilin 3A1 plays an essential role in prenyl pyrophosphate stimulation of human Vγ2Vδ2 T cells. J Immunol 191(3):1029–1042. https://doi.org/10.4049/jimmunol.1300658

    Article  CAS  PubMed  Google Scholar 

  14. Benyamine A, Le Roy A, Mamessier E et al (2016) BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia. Oncoimmunology 5(10):e1146843. https://doi.org/10.1080/2162402x.2016.1146843

    Article  PubMed  PubMed Central  Google Scholar 

  15. Döhner H, Estey E, Grimwade D et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447. https://doi.org/10.1182/blood-2016-08-733196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Diermayr S, Himmelreich H, Durovic B et al (2008) NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood 111(3):1428–1436. https://doi.org/10.1182/blood-2007-07-101311

    Article  CAS  PubMed  Google Scholar 

  17. Surapally S, Jayaprakasam M, Verma RS (2020) Curcumin augments therapeutic efficacy of TRAIL-based immunotoxins in leukemia. Pharmacol Rep 72(4):1032–1046. https://doi.org/10.1007/s43440-020-00073-7

    Article  CAS  PubMed  Google Scholar 

  18. Jan M, Leventhal MJ, Morgan EA et al (2019) Recurrent genetic HLA loss in AML relapsed after matched unrelated allogeneic hematopoietic cell transplantation. Blood Adv 3(14):2199–2204. https://doi.org/10.1182/bloodadvances.2019000445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Baragaño Raneros A, Martín-Palanco V, Fernandez AF et al (2015) Methylation of NKG2D ligands contributes to immune system evasion in acute myeloid leukemia. Genes Immun 16(1):71–82. https://doi.org/10.1038/gene.2014.58

    Article  CAS  PubMed  Google Scholar 

  20. Wu K, Zhao H, **u Y et al (2019) IL-21-mediated expansion of Vγ9Vδ2 T cells is limited by the Tim-3 pathway. Int Immunopharmacol 69:136–142. https://doi.org/10.1016/j.intimp.2019.01.027

    Article  CAS  PubMed  Google Scholar 

  21. Yang D, Zhang X, Zhang X et al (2017) The progress and current status of immunotherapy in acute myeloid leukemia. Ann Hematol 96(12):1965–1982. https://doi.org/10.1007/s00277-017-3148-x

    Article  CAS  PubMed  Google Scholar 

  22. Wilhelm M, Smetak M, Schaefer-Eckart K et al (2014) Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells. J Transl Med 12:45. https://doi.org/10.1186/1479-5876-12-45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu J, Gao H, Xu LP et al (2020) Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2(+) T cells activities after hematopoietic transplantation for blood malignancies. J Immunother Cancer 8(1). https://doi.org/10.1136/jitc-2019-000208

  24. **ang Z, Liu Y, Zheng J et al (2014) Targeted activation of human Vγ9Vδ2-T cells controls epstein-barr virus-induced B cell lymphoproliferative disease. Cancer Cell 26(4):565–576. https://doi.org/10.1016/j.ccr.2014.07.026

    Article  CAS  PubMed  Google Scholar 

  25. Harly C, Guillaume Y, Nedellec S et al (2012) Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human gammadelta T-cell subset. Blood 120(11):2269–2279. https://doi.org/10.1182/blood-2012-05-430470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gu S, Borowska MT, Boughter CT et al (2018) Butyrophilin3A proteins and Vgamma9Vdelta2 T cell activation. Semin Cell Dev Biol 84:65–74. https://doi.org/10.1016/j.semcdb.2018.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Palakodeti A, Sandstrom A, Sundaresan L et al (2012) The molecular basis for modulation of human Vγ9Vδ2 T cell responses by CD277/butyrophilin-3 (BTN3A)-specific antibodies. J Biol Chem 287(39):32780–32790. https://doi.org/10.1074/jbc.M112.384354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yamashiro H, Yoshizaki S, Tadaki T et al (2010) Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity. J Leukoc Biol 88(4):757–767. https://doi.org/10.1189/jlb.0309156

    Article  CAS  PubMed  Google Scholar 

  29. Rigau M, Ostrouska S, Fulford TS et al (2020) Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells. Science 367(6478):eaay5516. https://doi.org/10.1126/science.aay5516

    Article  CAS  PubMed  Google Scholar 

  30. Cano CE, Pasero C, De Gassart A et al (2021) BTN2A1, an immune checkpoint targeting Vγ9Vδ2 T cell cytotoxicity against malignant cells. Cell Rep 36(2):109359. https://doi.org/10.1016/j.celrep.2021.109359

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study is supported by the National Natural Science Foundation of China (No. 81770191).

Author information

Authors and Affiliations

  1. Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Bei**g Key Laboratory of Hematopoietic Stem Cell Transplantation, 11 **zhimen South Street, Bei**g, 100044, China

    Tianhui Dong, Ning Wu, Haitao Gao, Shuang Liang, **nyu Dong, Ting Zhao, Qian Jiang & Jiangying Liu

  2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Bei**g, China

    Shuang Liang

Authors
  1. Tianhui Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ning Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haitao Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. **nyu Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ting Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qian Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiangying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiangying Liu.

Ethics declarations

Ethics approval and consent to participate

All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The study protocols have been approved by the Ethical Committee of Peking University Institute of Hematology. All patients signed the consent forms.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dong, T., Wu, N., Gao, H. et al. CD277 agonist enhances the immunogenicity of relapsed/refractory acute myeloid leukemia towards Vδ2+ T cell cytotoxicity. Ann Hematol 101, 2195–2208 (2022). https://doi.org/10.1007/s00277-022-04930-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-022-04930-8

Keywords

Search

Navigation