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Expression of CD1d by myelomonocytic leukemias provides a target for cytotoxic NKT cells

Leukemia volume 17, pages 1068–1077 (2003)Cite this article

Abstract

Natural killer T (NKT) cells with an invariant T-cell receptor for α-galactosylceramide (αGalCer) that is presented by CD1d have been reported to be cytotoxic for myelomonocytic leukemia cells. However, the necessity for leukemia cell CD1d expression, the role of αGalCer, and the cytotoxic mechanisms have not been fully elucidated. We evaluated these issues with myeloid leukemia cells from 14 patients and purified NKT cells that were αGalCer/CD1d reactive. CD1d was expressed by 80–100% of cells in three of seven acute myeloid leukemias (AMLs) and by 28–77% of cells in five of six juvenile myelomonocytic leukemias (JMML). CD1d+ AML cells were myelomonocytic or monoblastic types, and CD1d+ JMML cells were differentiated and CD34−. Cytotoxicity required leukemia cell CD1d expression and was increased by αGalCer (P<0.0001) and inhibited by anti-CD1d mAb (P<0.001). The perforin/granzyme-B pathway of NKT cells caused up to 85% of cytotoxicity, and TNF-α, FASL, and TRAIL mediated additional killing. CD56+ NKT cells expressed greater perforin and were more cytotoxic than CD56 NKT cells without αGalCer (P<0.0001), but both subpopulations were highly and equally cytotoxic in the presence of αGalCer. We conclude that CD1d expression is stage-specific for myelomonocytic leukemias and could provide a target for NKT-cell-mediated immunotherapy.

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Acknowledgements

We thank Dr M Kronenberg (La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA) for αGalCer/hCD1d tetramers, Dr S Porcelli (Albert Einstein College of Medicine, Bronx, NY, USA) for anti-CD1d mAb 42.1, Kirin Brewery Co. Ltd. (Tokyo, Japan) for α-galactosylceramide (KRN 7000), and Dr J Buckley for providing Genetrix software for microarray analysis. We thank Dr B Perussia (Kimmel Cancer Center, Philadelphia, PA, USA) for critical review of the manuscript and Ms K Brakensiek and Drs Hong Wang and Yujun Yang for excellent technical assistance. This study was supported in part by NIH Grants CA81403, CA22794 (RCS); CA80916 (PDE); CA59318, HL-54850 (KW); and by the Neil Bogart Memorial Fund of the TJ Martell Foundation for Leukemia, Cancer, and AIDS Research.

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Pediatrics, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    L S Metelitsa & R C Seeger

  2. Division of Research Immunology and Bone Marrow Transplantation, Departments of Pediatrics, Molecular Microbiology and Immunology, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    K I Weinberg

  3. Division of Hematology-Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    P D Emanuel

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  1. L S Metelitsa
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Metelitsa, L., Weinberg, K., Emanuel, P. et al. Expression of CD1d by myelomonocytic leukemias provides a target for cytotoxic NKT cells. Leukemia 17, 1068–1077 (2003). https://doi.org/10.1038/sj.leu.2402943

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