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Wednesday, November 15, 2006
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NCI Researchers Induce Natural Killer Cells to Fight Liver Cancer in Mice

Two types of killer immune cells play divergent roles in fighting cancer located in the liver, according to a new study conducted by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). A team of researchers has shown that the activities of these cells can be manipulated by treating mice with interleukins — biological response chemicals that dial up or down the body’s natural immune response — to simultaneously stimulate helpful natural killer (NK) cells and alter the sometimes detrimental effects of natural killer T (NKT) cells to combat cancer in the liver. The study appears in the November 15, 2006, issue of Cancer Research.

“Initiation of an immune response against a tumor requires a complex set of events,” said NCI Director John Niederhuber, M.D. “Information that we gain from animal studies like this will provide insight into how the power of the immune system can be harnessed to develop new anticancer therapies.”

NK cells are specialized immune cells named for their inherent ability to respond swiftly to the invasion of pathogens without prior stimulation. They are able to recognize specific proteins on the surface of abnormal or infected cells and respond by releasing enzymes that poke holes in a target cell’s membrane and killing the cell. Tumor cells can also be besieged by NK cells if they lack the proper surface markers that designate them as being normal “self” cells. These markers tell patrolling NK cells that normal cells should not be attacked. Cancer cells sometimes have missing or altered markers on their surface, making them targets for NK cells.

NKT cells are another type of cell that share some characteristics with NK cells, but have only recently been appreciated for their role in immune defense. In contrast to NK cells, some NKT cells have been implicated in dampening the immune response to invading pathogens, rather than initiating an attack. However, both NK and NKT cells secrete, and in turn are controlled by, interleukins (ILs). Many different types of ILs, each carrying its own message between cells, are sent and received by a variety of cell types. IL-12 and IL-18 are two interleukins that, when received by NK and NKT cells, activate the cells’ immune response and relay the signal by triggering the release of another immune messenger molecule, interferon-gamma (IFN- ã).

Since large populations of NK and NKT cells are present in the liver, the NCI researchers examined the potential for using IL-12 and IL-18 together as a therapeutic regimen against tumors that originate in, or spread to, that organ. They showed that treating mice that had cancer with IL-18/IL-12 induced high levels of IFN- ã and greatly reduced the number of tumors in the liver.

Surprisingly, the researchers also noticed that treatment with IL-18/IL-12 not only increased numbers of NK cells in the liver, but also decreased the number of NKT cells that could be detected. Rather than restricting the immune system’s ability to fight cancer, altering or eliminating NKT cells further inhibited tumor growth. The researchers further explored this phenomenon by studying mice that had been engineered to lack NKT cells. They found that this tumor regression was enhanced when these mice were treated with interleukins. Conversely, reducing the population of NK cells decreased the anti-tumor effect of IL-18/IL-12 therapy in these animals.

Taken together, these results imply that anti-tumor activity induced in mice by IL-18 and IL-12 is dependent on both NK cells and IFN- ã, and is able to overcome the immunosuppressive effect of NKT cells. The researchers hope that enhancing NK cell function, while also eliminating or altering NKT cells, will improve cancer immunotherapy.

“We found that NKT cells actually have some inherent ability to inhibit the development of an immune response,” explained Robert Wiltrout, Ph.D., director of NCI’s Center for Cancer Research (CCR) and senior author of the study. “When we took NKT cells out of the picture, we got increased resistance to tumor formation and saw a benefit for the host, in this case a mouse, but hopefully someday also for a patient.”

"These are very promising findings for the immunotherapy of any type of cancer that is sensitive to killing by NK cells, as it does not require identification of molecules unique to the tumor,” said Jay A. Berzofsky, M.D., Ph.D., Chief, CCR Vaccine Branch. “In addition, if the IL-12/IL-18 treatment also diminishes the suppressive effects of NKT cells, it may provide the one-two punch needed to immunologically control cancer."

The liver is a target organ for the spread of many types of tumors, including kidney, colorectal, and breast cancer, all of which can be lethal in part based on their spread to vital organs such as the liver. Thus, approaches that enhance immune responses against cancer in the liver might be beneficial for cancer patients with tumors that arise in, or metastasize to, the liver.

For more information on Dr. Wiltrout’s research, go to http://ccr.cancer.gov/Staff/staff.asp?profileid=5710

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.


*Subleski JJ, Hall VL, Back TC, Ortaldo JR, Wiltrout RH. Enhanced Antitumor Response by Divergent Modulation of NK and NKT Cells in the Liver. Cancer Research 2006; Vol. 66, Issue 22.
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