Credit: Bjorn Onfelt/Dan Davis
Inhibiting STAT3 in natural killer (NK) cells can kill leukemia in two ways, according to research published in Blood.
In mouse models lacking STAT3, NK cells were still able to develop normally, and the loss of STAT3 prompted an increase in antileukemic activity.
Mice whose NK cells lacked STAT3 showed a reduction in tumor growth and an increase in survival compared to controls.
Similar results were observed in mouse models of melanoma.
“We were expecting the loss of STAT3 to make the NK cells less efficient,” said study author Dagmar Gotthardt, of the University of Veterinary Medicine, Vienna (Vetmeduni Vienna).
“Instead, it makes them even more potent killers. Inhibiting STAT3 could thus help cancer patients in two ways: both stopping the cancer cells from dividing and helping the patients’ NK cells to fight them more efficiently.”
Researchers are already attempting to develop STAT3 inhibitors for cancer therapy, but their effect on NK cells was not known.
So Gotthardt and her colleagues assessed the function of STAT3 in NK cells using Stat3Δ/ΔNcr1-iCreTg mice, whose NK cells lack STAT3.
The team discovered that NK cells lacking STAT3 still develop and mature normally, but they do have alterations in the kinetics of interferon-γ production. In addition, there is a consistent increase in levels of perforin, granzyme B, and DNAM-1 in the absence of STAT3.
The investigators also found the loss of STAT3 in NK cells improved tumor surveillance against leukemia.
They injected v-abl1 leukemic cell lines into Stat3fl/fl and Stat3Δ/ΔNcr1-iCreTg mice. After 12 days, the Stat3fl/fl mice had large tumors, but there was “a pronounced reduction of tumor mass” in the Stat3Δ/ΔNcr1-iCreTg mice.
The researchers then injected 2 individually derived leukemic cell lines into Stat3fl/fl and Stat3Δ/ΔNcr1-iCreTg mice. And the results were similar to those of the previous experiment. Stat3Δ/ΔNcr1-iCreTg mice survived significantly longer than Stat3fl/fl mice (P=0.0002).
Next, the investigators injected newborn mice with a replication-incompetent ecotropic retrovirus encoding for v-abl, as this model more closely mimics the development of human disease.
Again, there was a significant difference in survival between Stat3fl/fl mice and Stat3Δ/ΔNcr1-iCreTg mice (P=0.007). All Stat3fl/fl mice died, but 20% of Stat3Δ/ΔNcr1-iCreTg mice were still alive at 150 days post-injection, and their disease latency was significantly delayed.
The researchers also found that loss of STAT3 in NK cells led to an increase in killing activity against melanoma cells. They said the decrease in metastasis caused by melanoma cells was especially dramatic and confirmed that NK cells lacking STAT3 are extremely efficient killers of tumor cells.
