HIF-1a: The killer cell “brake"

Researchers are finding another approach to attack therapy-resistant tumors. If the hypoxia-induced factor-1α is switched off in natural killer (NK) cells, tumor growth slows down.

Cascade of antitumor factors is activated in the observed process

Researchers are finding another approach to attack therapy-resistant tumors. If the hypoxia-induced factor-1α is switched off in natural killer (NK) cells, tumor growth slows down. 

Cancer immunotherapy uses the body's own defense system to destroy cancer cells. Research focuses mainly on the acquired, targeted immune defense, with the main players being T and B lymphocytes, which can react specifically to antigens.

However, NK cells, which are part of the innate immune system, are also attracting increasing attention in the fight against tumors. Their name says it all: they form an unspecific, rapid, and natural defense against altered endogenous cells and are therefore one of the first lines of defense in the fight against infections and cancer. Unfortunately, however, NK cells quickly lose their anti-tumor activity as soon as they have entered tumor tissue.

Pulling the handbrake on...

Scientists at the Mannheim Medical Faculty of the University of Heidelberg, led by Professor Dr. Adelheid Cerwenka, and the German Cancer Research Centre (in German: Deutschen Krebsforschungszentrums), led by Professor Dr. Thomas Höfer, have now succeeded in identifying a key molecule that slows down the activity of natural killer cells in tumor defense. Releasing this brake could be a promising strategy to improve NK-cell-based immune therapies against solid tumors.

Hypoxia is a common feature of solid tumors. The cells respond to the lack of oxygen by upregulating the hypoxia-induced transcription factor-1α (HIF-1α). By specifically switching off this molecule in NK cells, the activity of the killer cells was greatly increased, which slowed down the growth of tumors in the mouse model.

Inhibition of HIF-1α triggers an antitumor cascade

Single-cell RNA sequencing of NK cells that have migrated into the tumor showed that in NK cells without HIF-1α, a whole cascade of factors effective against the tumor is triggered. The inhibition of HIF-1α apparently releases and anti-tumor activity of the NK cells, which could be used for cancer therapy.

Professor Dr. Adelheid Cerwenka at the Mannheim Institute for Innate Immunoscience (MI3), part of the Mannheim Medical Faculty, Germany, is investigating NK-cell-based therapies against cancer. "The reason why NK cells quickly lose their aggressiveness as soon as they have migrated into tumor tissue is the lack of oxygen in solid tumors. If we succeed in overcoming this braking mechanism, the killer cells can develop their full potential in the fight against the tumor," Prof. Cerwenka explained.

From the transcriptional pattern of individual NK cells, the scientists found that switching off HIF-1α led to the increased expression of activation markers and effector molecules and to increased activation of the NF-κB signaling pathway. NF-κB is an important transcription factor that plays a key role in controlling the anti-tumor activity of immune cells.

Application in humans

Not only cultured mice NK cells, but also human NK cells showed an increased antitumor reactivity when HIF-1α was switched off or inhibited. In addition, the scientists were able to show that this activity depended on the presence of interleukin 18, an endogenous regulator protein of the immune system.

"Our study shows that the transcription factor HIF-1α acts as an immune control point that inhibits the natural killer cells in the tumor's microenvironment. Based on these results, we are now investigating in human NK cells whether we can use the elimination of HIF-1α for a therapeutic application," Dr. Ana Stojanovic, one of the main authors, outlined as the road ahead.