Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction
Abstract
Natural killer (NK) cells play an important role in tumor-cell clearance, particularly against leukemia, as shown by killer cell inhibitory receptor (KIR)–mismatched allogeneic stem cell transplantation. Analysis of in vitro IL-2–expanded NK cells from patients with myelocytic/monocytic acute myeloid leukemia (AML-NK cells) has revealed poor cytolytic functions because of deficient expression of pivotal activation molecules—the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. To exclude the possibility that this observation was caused by the in vitro amplification of a small NCRdull population, we analyzed the AML-NK phenotype directly, without any in vitro expansion. We first confirmed that the NCRdull phenotype was not an in vitro artifact. Moreover, analysis of a large population of AML patients allowed us to demonstrate that phenotype was not restricted to a French-American-British (FAB) subtype and was not associated with a particular cytogenetic abnormality. Our longitudinal study of AML patients showed that the NCRdull phenotype was acquired during leukemia development because we observed its complete (for NKp46) or partial (for NKp30) reversibility in patients achieving complete remission (CR). Reversibility of the NCRdull phenotype after CR suggested that leukemia cells might be involved in NCR down-regulation. In agreement with this hypothesis, direct contact between leukemic blasts and NK cells (but not leukemia-cell supernatants) induced loss or decrease in NKp30 and NKp46 expression while impeding NKp44 induction by IL-2. We excluded the major implication of TGF-β in NCR down-regulation. Although the clinical antitumor value of NK cells is clearly demonstrated in allogeneic stem cell transplantation, the role of NK cells in autologous transplantation is not proved. Interestingly, we observed a correlation between the NCRdull phenotype and poor survival in AML patients, suggesting that NK-deficient activation caused by NCR down-regulation could play a role in patient outcome. The prognostic value of NCR expression is discussed, and pathophysiologic implication of the NCR phenotype will be further investigated in a larger study.
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NKp30, NKp46, and DNAM-1 are NK activation receptors involved in the recognition and lysis of different tumors, such as hematological malignancies, melanoma, and ovarian cancer.
“Moreover, NKp30, NKp46, and DNAM-1 are NK activation receptors involved in the recognition and lysis of different tumors, such as hematological malignancies [82], melanoma [83], and ovarian cancer [84].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [82]
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- Authors
- Fauriat, C., Just-Landi, S., Mallet, F., Arnoulet, C., Sainty, D., Olive, D., & Costello, R. T.
- Affiliations
- Inserm (FR)
- Laboratoire d'Immunologie des Tumeurs, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixté de Recherche (UMR) 599, and
- Institut Paoli-Calmettes (FR)
- Aix-Marseille Université (FR)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-08-29
- Volume
- 109
- Issue
- 1
- Pages
- 323-330
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1964982854
- Cited by
- 380
- References
- 30
- Citations by year
- 2026: 4 · 2025: 16 · 2024: 20 · 2023: 24 · 2022: 17 · 2021: 28 · 2020: 29 · 2019: 21 · 2018: 20 · 2017: 34 · 2016: 21 · 2015: 21 · 2014: 16 · 2013: 27 · 2012: 18
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation pour la Recherche Médicale
- Ligue Contre le Cancer
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- natural cytotoxicity receptors, natural killer cells, acute myeloid leukemia, NKp30, NKp44, NKp46, leukemia cells, NK cell activation, complete remission, prognostic factors, survival, TGF-beta, interleukin-2, NK cell cytotoxicity, autologous transplantation
- MeSH terms
- Acute Disease, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cell Differentiation, Cell Transformation, Neoplastic, Cytotoxicity, Immunologic, Female, Hematopoietic Stem Cells, Humans, Interleukin-2, Killer Cells, Natural, Leukemia, Myeloid, Male, Membrane Glycoproteins, Middle Aged, Neoplasm Proteins, Receptors, Immunologic, Remission Induction, Tumor Cells, Cultured, Neoplastic Stem Cells, Gene Expression Regulation, Leukemic, Survival Analysis, Coculture Techniques, Kaplan-Meier Estimate, Natural Cytotoxicity Triggering Receptor 1, Natural Cytotoxicity Triggering Receptor 3, Natural Cytotoxicity Triggering Receptor 2
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