Activated invariant natural killer T cells directly recognize leukemia cells in a CD1d-independent manner
Open Access
- 1 July 2020
- journal article
- research article
- Published by Wiley in Cancer Science
- Vol. 111 (7), 2223-2233
- https://doi.org/10.1111/cas.14428
Abstract
Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of V alpha 24 and V beta 11 in humans. iNKT cells specifically recognize glycolipid antigens such as alpha-galactosylceramide (alpha GalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as alpha GalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d.Keywords
Funding Information
- Masato Kawano Memorial Public Interest Foundation for Promotion of Pediatrics
- Japan Society for the Promotion of Science London (KAKENHI/18K16108)
- Chiba University (Therapeutics Research Initiative Grant/2018‐Y7,)
This publication has 44 references indexed in Scilit:
- α-GalCer and iNKT Cell-Based Cancer Immunotherapy: Realizing the Therapeutic PotentialsFrontiers in Immunology, 2019
- Invariant Natural Killer T Cells in Immune Regulation of Blood Cancers: Harnessing Their Potential in ImmunotherapiesFrontiers in Immunology, 2017
- Natural Killer T Cell-Targeted Immunotherapy Mediating Long-term Memory Responses and Strong Antitumor ActivityFrontiers in Immunology, 2017
- Natural Killer T Cells in Cancer ImmunotherapyFrontiers in Immunology, 2017
- The Role of Invariant Natural Killer T Cells in Dendritic Cell Licensing, Cross-Priming, and Memory CD8+ T Cell GenerationFrontiers in Immunology, 2015
- NKT Cells as an Ideal Anti-Tumor ImmunotherapeuticFrontiers in Immunology, 2013
- Targeting natural killer cells and natural killer T cells in cancerNature Reviews Immunology, 2012
- CD1d expression level in tumor cells is an important determinant for anti-tumor immunity by natural killer T cellsLeukemia & Lymphoma, 2006
- NKT cells: what's in a name?Nature Reviews Immunology, 2004
- Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK CellsThe Journal of Immunology, 2001