A Japanese brewery, an Okinawan sea sponge, and some clever detective work have enabled an international research team based at the University of Chicago to solve a biological mystery, and the solution suggests a novel way to boost the body's defenses against cancer.
In Science Express, the online early-publication version of the journal Science, the researchers provide evidence that a sugary lipid known as iGb3 plays a key role in regulating the response of natural killer T cells, a component of the immune system that plays an important role in preventing cancer, fighting infections and perhaps triggering or avoiding autoimmune diseases.
Discovered less than 10 years ago, natural killer (NK) T cells are unusual because they target lipids, often bound to carbohydrates, rather than proteins. When presented with a lipid that may signal a threat, they pump out chemical signals, such interferon-gamma and interleukin-4, which tell other components of the immune system to rid the body of these invaders.
Mice with defects in this system are prone to cancer and susceptible to infections. On the other hand, misdirected NKT cells may play a role in autoimmune diseases, such as type-1 diabetes.
"Until now we had no idea what activated NKT cells except for one curious compound, a glycosphingolipid derived from a marine sponge," said study author Albert Bendelac, "but once we learned that this compound could prevent the spread of cancer in mice, a lot of people became very interested."
Bendelac, MD, PhD, a professor of pathology at the University of Chicago, is one of only a handful of immunologists who concentrate on NKT cells. Scientists know a great deal about how the immune system recognizes proteins, but comparatively little about this type of cell or the mechanisms the immune system uses to sort out lipids.
NKT cells are also odd in that they fall somewhere between the brute force of innate immunity and the flexible sophistication of adaptive immunity. They appear to have an ingrained ability to recognize some bacterial lipids. At the same time, they express less-variable versions of T-cell receptors. These stripped-down receptors enable NKT cells to respond to a limited array of lipid or carbohydrate antigens when presented in certain ways.
The only substance known to fully activate NKT cells through these receptors was the glycosphingolipid derived from an Okinawan sea sponge Agelas mauritianus. In the 1990s, researchers at the Kirin Brewery in Japan found this molecule alpha-Galactosyl-ceramide, by performing a pharmaceutical screen for natural compounds with anti-tumor activity. While this compound exhibited potent anti-cancer activity in vivo, there was no clue about the mechanism of action until researchers discovered that it was recognized by NKT cells.
A purified synthetic version, known a-GalCer or KRN 7000, is now in phase-2 human clinical trials for several tumor types. One problem with _a-GalCer, however, is that it can over-stimulate NKT cells. After a burst of activity and rapid secretion of interferon-gamma, NKT cells driven by a-GalCer essentially "burn out," disappearing from the circulation for weeks.
"This sponge glycolipid, _a-GalCer, is not a substance seen in mammals," said Bendelac. "But it pointed us toward similar molecules in our hunt for the natural substance that activates NKT cells."
Finding the natural activator--what immunologist call the endogenous ligand--for these cells is crucial to understanding their biology, he added, and might provide a gentler and more enduring way to get them to fight tumors.
Bendelac's team developed several approaches to identify the endogenous ligand. One crucial clue came from the discovery of genetically deficient mice that have almost no NKT cells. Bendelac's team found that these mice are unable to make an enzyme required to produce iGb3. Mice that lack this enzyme have a severe NKT cell deficiency, and are cancer prone.
"We don't yet know the real function of iGb3, how it works or even how to find and measure it in the body," Bendelac said, "but we suspect is serves as an alarm of some kind. It may be produced by cells that are stressed--damaged by an infection or transformed into cancer cells. Then it alerts the immune system to the presence of cells in trouble."
Activating NKT cells may be particularly valuable for preventing or treating cancers that spread to the liver, where NKT cells are most common.
Understanding the role of iGb3 may also provide clues about autoimmune disease. NKT cells play an important, although still poorly understood, role in regulating all sorts of immune responses. Defects in the system may allow the body to attack itself, leading to chronic inflammation or tissue damage.
"It has been extremely difficult to explore the mechanisms that govern the recruitment, activation and development of NKT cells without knowledge of the natural antigens recognized by these cells," said Bendelac. "Because of their role in regulating a range of diseases, this has been a source of intense research and speculation for years."
The National Institutes of Health supported this research. Additional authors were lead author Dapeng Zhou, plus Jochen Mattner, Yuval Sagiv and Kelly Hudspeth of the University of Chicago; Carlos Cantu, Nicolas Schrantz and Luc Teyton of the Scripps Research Institute; Ning Yin, Ying Gao and Paul Savage of Brigham Young University; Yunping Wu, Tadashi Yamashita and Richard Proia of the NIH; Susan Teneberg of Goteborg University, Sweden; Dacheng Wang of the Chinese Academy of Sciences; and Steven Levery of the University of New Hampshire.
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