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The HOXB4 homeoprotein improves ex vivo generation of functional human NK-cell progenitors

Leukemia volume 21, pages 1836–1839 (2007)Cite this article

Natural killer (NK) cells are cellular components of the innate immune system that play critical roles in protection against cancer and display potent antileukemia and antirejection activities. New therapeutic protocols aiming at improving the treatment of leukemias and cancers may commonly comprise the use of NK cells and thus require the availability of sufficient amounts of such cells.1, 2 Common methods for NK-cell collection and expansion require serial leukapheresis that allow collection of mature NK cells from blood followed by long-term growth factor stimulation or can include classical ex vivo long-term expansion of human CD34+ progenitor cells followed by NK-cell differentiation of the expanded cells.3, 4 Here, we report a method for efficient ex vivo expansion of human NK progenitors, exclusive of the addition of exogenous cytokines or retrovirus gene transfer and based on supply of the HOXB4 transcription factor. In a previous work, our group had designed a protocol that allowed direct delivery of this homeoprotein into human hematopoietic stem cells (HSCs).5 This model led to ex vivo expansion of human HSCs and myeloid progenitors with further maintenance of in vivo lympho-myeloid differentiation potential of HSCs.5 However, NK progenitor expansion was not established. Thus, using a similar strategy, we demonstrate that HOXB4 protein transfer into CD34+CD38lo/− immature human hematopoietic cells generates high number of NK progenitors able to develop functional mature NK cells.

Taken together, our results show that transfer of the HOXB4 protein into CD34+CD38lo/− immature cells5 efficiently promotes NK progenitor cell expansion as compared to day-0 nonexpanded CD34+CD38lo/− cells and to control co-cultures. Moreover, this ex vivo expansion of progenitor cells should be considered as a powerful strategy as compared to NK-cell progenitor expansion performed from classical long-term culture of hematopoietic progenitors.4 Such expansion mediated by HOXB4 does not impair the functionality of resulting NK cells since, when generated from progenitors expanded by HOXB4, they can be further activated to fully differentiated NK cells that display cytotoxic activity against leukemic cells. The use of purified recombinant HOXB4 protein will be required in the perspective of NK-cell adoptive immunotherapy of malignancies. Indeed, activated NK cells represent potential therapy in hematopoietic malignant disorders, during or after allogenic bone marrow transplantation. NK cells are now recognized as important cytotoxic effectors involved in the graft-versus-leukemia (GvL) and in the maintenance of remission in a minimal residual disease setting after autologous transplantation. The expansion model we developed could also provide a promising additional tool for immunotherapy prospects particularly in patients with NK progenitor cell deficiencies.

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Acknowledgements

This work was supported by grants from the Agence Nationale pour la Recherche (ANR) and the Ligue Nationale contre le Cancer (LNCC). We thank Françoise Pflumio, Sylvie Gisselbrecht and Béla Papp for helpful discussions, Micaël Yagello for flow cytometry cell sorting, Azzedine Yacia and Sylvie Da Rocha for technical assistance.

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Authors and Affiliations

  1. Département d'Hématologie, Institut Cochin, Paris, France

    R Haddad, I Vigon, S Fichelson & S Amsellem

  2. INSERM U567, Paris, France

    R Haddad, I Vigon, S Fichelson & S Amsellem

  3. CNRS UMR 8104, Paris, France

    R Haddad, I Vigon, S Fichelson & S Amsellem

  4. Université Paris 5, Faculté de Médecine René Descartes UM 3, Paris, France

    R Haddad, I Vigon, S Fichelson & S Amsellem

  5. INSERM U753, Institut Gustave Roussy, Villejuif, France

    A Caignard & G Visentin

  6. INSERM, Institut Gustave Roussy, Villejuif, France

    S Amsellem

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  1. R Haddad
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  2. A Caignard
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  3. G Visentin
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Correspondence to S Fichelson.

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Haddad, R., Caignard, A., Visentin, G. et al. The HOXB4 homeoprotein improves ex vivo generation of functional human NK-cell progenitors. Leukemia 21, 1836–1839 (2007). https://doi.org/10.1038/sj.leu.2404725

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