|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
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
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site at http://www.cancer.gov or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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