Abstract
Infusion of ex vivo expanded and cytokine-activated natural killer (NK) cells is a promising alternative way to treat multiple myeloma (MM). However, the tumor microenvironment (TME) may suppress their function. While reduced glucose availability is a TME hallmark of many solid tumors, glucose levels within the TME of hematological malignancies residing in the bone marrow (BM) remain unknown. Here, we measured glucose levels in the BM of MM patients and tested the effect of different glucose levels on NK cells. BM glucose levels were measured using a biochemical analyzer. Compared to the normal range of blood glucose, BM glucose levels were lower in 6 of 9 patients (479-1231 mg/L; mean=731.8 mg/L). The effect of different glucose levels on NK cell cytotoxicity was tested in 4-hour cytotoxicity assays with tumor cells. 500 mg/L glucose (representing low range of MM BM) during the 4-hour cytotoxicity assay did not negatively affect cytotoxicity of activated NK cells, while higher glucose concentrations (4000 mg/L) diminished NK cell cytotoxicity. Since clinical application of NK cell therapy might require ex vivo expansion, expanded NK cells were exposed to a range of glucose concentrations from 500-4000 mg/L for a longer period (4 days). This did not reduce cytotoxicity or IFN-γ secretion nor affected their phenotypic profile. In summary, low glucose concentrations, as found in BM of MM patients, by itself did not compromise the anti-tumor potential of IL-2 activated NK cells in vitro. Although follow up studies in models with a more complex TME would be relevant, our data suggest that highly activated NK cells could be used to target tumors with a reduced glucose environment.
Highlights
In the last decade, considerable effort has been put in the development of natural killer (NK) cell-based immunotherapy to treat cancer patients due to the clinical potential and good safety profile of NK cells
We tested the effect of the glucose levels as observed in bone marrow (BM) of MM patients, the glucose levels in normal blood, and the glucose levels used in culture media on the cytotoxic capacity of NK cells derived from healthy donors
As glucose is the primary fuel for NK cells, we aimed to gain more insight on the effect of glucose levels in the tumor microenvironment (TME) of MM on overnight cytokine-activated or ex vivo expanded NK cells and NK Cells Withstand Glucose-Limited Environment B
Summary
Considerable effort has been put in the development of NK cell-based immunotherapy to treat cancer patients due to the clinical potential and good safety profile of NK cells. Ex vivo expanded and cytokine-activated NK cells are used to create highly cytotoxic NK cells Despite these initially hopeful clinical outcomes, the therapeutic efficacy of NK cell-based immunotherapy could be improved by increasing NK-cell numbers, enhancing NK-cell activation, improving NKcell tumor-targeting capacity, and improving in vivo NK-cell persistence [1]. The metabolic microenvironment of tumor cells could inhibit the antitumor response of immune cells such as cytotoxic T cells and NK cells [14] To sustain their growth and survival, tumor cells frequently undergo metabolic reprogramming, allowing the enhancement of glucose uptake and metabolism. This process takes place within a hypoxic region and in the area where sufficient oxygen is available, a phenomenon known as aerobic glycolysis or “the Warburg effect” [15]. There is not much known about glucose levels within the microenvironment of hematological cancers
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