Activated invariant natural killer T cells directly recognize leukemia cells in a CD1d‐independent manner

Apr 24, 2020Cancer science

Activated invariant natural killer T cells directly recognize leukemia cells without relying on CD1d

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Abstract

Activated cells recognize leukemia cells in a CD1d-independent manner.

iNKT cells degranulated and released Th1 cytokines when interacting with both CD1d-negative leukemia cells and CD1d-positive cells presenting glycolipid antigens.
Natural killer cell-activating receptors enhanced iNKT cell cytotoxicity but were not required for recognizing CD1d-negative leukemia cells.
The T cell receptor (TCR) was essential for the CD1d-independent recognition and cytotoxicity of leukemia cells.
iNKT cells showed a preference for targeting myeloid malignancies over acute lymphoblastic leukemia.
These findings suggest a novel anti-tumor mechanism for iNKT cells that could have clinical implications for treating leukemia without relying on CD1d expression.

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Invariant natural killer T () cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vβ11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) 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 αGalCer-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.

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