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A Novel Feeder-free System for Mass Production of Murine Natural Killer Cells In Vitro
Published on: January 9, 2018
Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function
Miroslaw J Szczepanski1, Marta Szajnik, Ann Welsh
1University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232 USA.
Background:
Natural killer cell cytotoxicity is decreased in patients with acute myeloid leukemia in comparison to that in normal controls. Tumor-derived microvesicles present in patients' sera exert detrimental effects on immune cells and may influence tumor progression.
Design And Methods:
We investigated the microvesicle protein level, molecular profile and suppression of natural killer cell activity in patients with newly diagnosed acute myeloid leukemia.
Results:
The patients' sera contained higher levels of microvesicles compared to the levels in controls (P<0.001). Isolated microvesicles had a distinct molecular profile: in addition to conventional microvesicle markers, they contained membrane-associated transforming growth factor-β1, MICA/MICB and myeloid blasts markers, CD34, CD33 and CD117. These microvesicles decreased natural killer cell cytotoxicity (P<0.002) and down-regulated expression of NKG2D in normal natural killer cells (P<0.001). Sera from patients with acute myeloid leukemia contained elevated levels of transforming growth factor-β, and urea-mediated dissociation of microvesicles further increased the levels of this protein. Neutralizing anti-transforming growth factor-β1 antibodies inhibited microvesicle-mediated suppression of natural killer cell activity and NKG2D down-regulation. Interleukin-15 protected natural killer cells from adverse effects of tumor-derived microvesicles.
Conclusions:
We provide evidence for the existence in acute myeloid leukemia of a novel mechanism of natural killer cell suppression mediated by tumor-derived microvesicles and for the ability of interleukin-15 to counteract this suppression.
Insights
Tumor-derived microvesicles in acute myeloid leukemia patients suppress natural killer cell function. Interleukin-15 can counteract this suppression, offering a potential therapeutic strategy against this hematologic malignancy.
Area of Science:
- Immunology
- Hematology
- Oncology
Background:
- Natural killer (NK) cell cytotoxicity is diminished in acute myeloid leukemia (AML) patients.
- Tumor-derived microvesicles in AML sera negatively impact immune cells and may promote disease progression.
Purpose of the Study:
- To investigate the characteristics of microvesicles in AML patients.
- To determine the effect of these microvesicles on NK cell activity.
- To explore potential counteracting agents.
Main Methods:
- Quantified microvesicle levels in AML patient sera compared to controls.
- Analyzed the molecular profile of isolated microvesicles.
- Assessed the impact of microvesicles on NK cell cytotoxicity and NKG2D expression.
- Investigated the role of transforming growth factor-β1 (TGF-β1) and the effect of interleukin-15 (IL-15).
Main Results:
- AML patients exhibited significantly higher serum microvesicle levels.
- Microvesicles contained AML-specific markers (CD34, CD33, CD117), TGF-β1, and MICA/MICB.
- Microvesicles suppressed NK cell cytotoxicity and NKG2D expression.
- Neutralization of TGF-β1 and IL-15 treatment reversed these suppressive effects.
Conclusions:
- A novel mechanism of NK cell suppression by tumor-derived microvesicles in AML is identified.
- Interleukin-15 demonstrates potential in counteracting microvesicle-mediated NK cell suppression in AML.
