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Immunologic manipulation in AML: from bench to bedside

Leukemia volume 16, pages 736–737 (2002)Cite this article

The development of immunotherapeutic strategies for the treatment of leukemia and other cancers has long been of interest. Natural killer (NK) cells represent one component of the innate immune system and have the ability to both lyse target cells and produce immunoregulatory cytokines. Thus, these large granular lymphocytes have been the subject of intense investigation for their antitumor effects. Human NK cells comprise approximately 10–15% of all peripheral blood lymphocytes and are defined by the presence of the CD56 cell surface antigen and the lack of CD3.1 Two subsets of NK cells can be distinguished based on their cell surface density of CD56. The majority (∼90%) of human NK cells are CD56dim and express high levels of Fc RIII (CD16), which mediates antibody- dependent cellular cytotoxicity, while a minority (∼10%) of NK cells are CD56bright CD16dim/neg.2 NK cells have the unique ability to lyse tumor target cells without prior sensitization, in contrast to T lymphocytes, which depend on activation and presentation of specific antigens associated with HLA molecules to elicit a cytotoxic effect. Because of this fact, there has been a great deal of interest in understanding the mechanisms whereby NK cells mediate their cytotolytic effects. It is now clear that NK receptors (NKRs) for MHC class I molecules are critical for the recognition of normal vs transformed and/or foreign cells. In the setting of therapy for acute myeloid leukemia (AML) and other hematologic malignancies, there is now good evidence to suggest that mismatch of donor NKRs and recipient class I molecules in haplotype- mismatched BMT may have a beneficial effect when that mismatch is in the donor vs leukemia direction.3 Thus, immunotherapeutic strategies targeting NK cells have the potential to be beneficial for the treatment of leukemia.

It has been known for decades that NK cells develop within the bone marrow (BM) microenvironment and numerous studies have definitively identified the cytokine interleukin (IL)-15 as the critical factor necessary for the development of human and murine NK cells.4,5 IL-15 is produced by a variety of cell types, including normal BM stroma and antigen-presenting cells, and can induce NK cell differentation from human hematopoietic progenitor cells (HPCs) in the absence of other cytokines in vitro.6 IL-15 shares common signaling receptor subunits with the T cell-derived cytokine IL-2, including the IL-2/15R and common gamma chain (γc), which together form an intermediate-affinity heterodimeric receptor complex (IL-2/15Rβγ). However, IL-15 and IL-2 also each utilize private alpha chains (IL-15Rα and IL-2Rα) that can confer high affinity binding to their respective heterotrimeric receptors, IL-15Rαβγ and IL-2Rαβγ. Although IL-2 is produced primarily in the periphery and is not required for NK cell development, as the result of their shared receptor usage, IL-2 can elicit many of the same effects as IL-15 when administered in vivo. In addition, ligands for the receptor tyrosine kinases flt3 and c-kit can increase the NK cell precursor frequency of HPCs through up-regulation of the IL-15R complex in vitro,6,7 and in vivo.8 Clinical trials have demonstrated that treatment of leukemia patients with low-dose IL-2 can safely drive NK cell development and expansion.9 However, administration of additional NK differentiation factors such as flt3 ligand or c-kit ligand in combination with IL-2 has the potential to enhance NK cell differentiation and expansion in the setting of malignancy.

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  1. Department of Internal Medicine and the Comprehensive Cancer Center, The College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA

    MA Cooper & MA Caligiuri

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  1. MA Cooper
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This paper is part of a series of keynote addresses to be published in Leukemia. They were presented at the Acute Leukemia Forum, San Francisco, 20 April 2001. Supported by an unrestricted educational grant from Immunex.

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Cooper, M., Caligiuri, M. Immunologic manipulation in AML: from bench to bedside. Leukemia 16, 736–737 (2002). https://doi.org/10.1038/sj.leu.2402411

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