A Novel Role for TGFβ in Boosting Anti-tumor Functions of Natural Killer Cells

January 17, 2019
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NK cells are an important part of the strategy to manipulate the immune system to fight cancer. Making TGFβ-resistant NK cells is a step toward improving their activity against it.

Natural killer (NK) cells are a component of the innate immune system that mediates the cell death of virally-infected or cancerous cells through a release of cytotoxic molecules including cytokines.  Cancer cells fight back by making their own cytokines – such as transforming growth factor beta (TGFβ) – which is known to negatively alter NK cell function.

“We grew our NK cells in TGFβ to select out the ones that were TGFβ-resistant. We didn’t expect that the growth would remain intact,” says Dean Lee, MD, PhD, director of the Cellular Therapy and Cancer Immunology Program at Nationwide Children’s Hospital. “Since they grew just fine in TGFβ, we tested them for killing while in the presence of TGFβ. Cells grown the normal way were stopped from killing by TGFβ, but surprisingly, cells grown with TGFβ now seem to be resistant to it.”

Dr. Lee and his team previously developed a landmark method for growing NK cells for cancer immunotherapy, still widely used today.  Now Dr. Lee and his colleagues have applied their growth method to generate specialized TGFβ-resistant NK cells, through a process termed TGFβ imprinting (TGFβi).

“The idea was to get NK cells that are resistant to TGFβ because they need that resistance once they get to a tumor.  The NK cells work really great for leukemia, but one of the problems in a solid tumor is all this TGFβ that’s there,” says Dr. Lee.

Many types of tumors produce TGFb, which acts as a suppressor of the anti-tumor immune response, rendering NK cells and other immune cells virtually ineffective after exposure to high levels in the tumor microenvironment.

Dr. Lee’s recent study on TGFβi NK cells, published in Cancers, demonstrates for the first time that chronic co-stimulation of NK cells with IL-2 and TGFβ during NK cell growth and activation produces pro-inflammatory NK cells. Unlike regular NK cells, which are sensitive to TGFβ, resulting in loss of cytotoxicity and cytokine secretion, the TGFβi NK cells exhibit enhanced cytokine secretion and expression of signaling molecules.  This phenomenon persists at least a month post-treatment, and improves their anti-tumor response in some tumor cell types, suggesting they might be used as a therapeutic.

“They will likely work better than other NK cells in tumors that make lots of TGFβ.  Not every tumor does, so we might need to screen your tumor first to see if yours is making TGFβ,” says Dr. Lee.

In terms of how TGFβi happens in NK cells, the team has discovered what appears to be a feedback loop that suppresses an important component of TGFβ signaling.  They are conducting further studies into the regulation of NK cell to genes to answer more questions about this mechanism.

“This research is an important piece of trying to understand how can we make our immune systems better,” says Dr. Lee.  “Ultimately, I’d like explore settings where we can cure cancer by giving back your own supercharged NK cells to help boost your immunity.  We have great success in pediatrics with chemotherapy – we’re curing 70 percent of all the kids who get cancer. But chemotherapy also kills off these important immune cells, and we just wait for your body to restore them. What if we could cure 90 or 95 percent if we just didn’t wait, but we helped your body do it?”



Foltz JA, Moseman JE, Thakkar A, Chakravarti N, Lee DA. TGFB imprinting during activation promotes natural killer cell cytokine hypersecretion. Cancers (Basel). 2018 Nov 5;10(11):E423.

Image credit: Nationwide Children’s