Hybrid Cancer-Killing Cell Discovered in Mice - May Have Human Counterpart

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Newly Discovered Killer Cell Fights Cancer

A mouse immune cell that plays dual roles as both assassin

and messenger, normally the job of two separate cells, has been

discovered by an international team of researchers from the United

States and France. The discovery has triggered a race among

scientists to find a human equivalent of the multitasking cell,

which could one day be a target for therapies. that seek out and

destroy cancer.

(http://www.sciencedaily.com/releases/2006/03/060303203640.htm#)

" In the same way that intelligence and law enforcement

agencies can face

deadly threats together instead of separately, this one

cell combines the ability to kill foreign pathogens and distribute

information about that

experience, " says Drew Pardoll, M.D., Ph.D., the Seraph

Professor of _Oncology_

at the s Hopkins Kimmel Cancer Center.

" We think this hybrid cell speeds up immune reactions and

makes the system more efficient, " adds Pardoll, whose findings are

reported in the February issue of Nature Medicine.

The Hopkins investigators speculate that the hybrid, dubbed

" IKDC " for interferon-producing killer dendritic cell, has been

missed by cancer biologists because it is rare, making up one-tenth

of cells in the spleen with similar features, such as other dendritic

cells, according to

Housseau, Ph.D.,

research associate at Hopkins' Kimmel Cancer Center and

member of Pardoll's immunology laboratory.

Most of the immune system typically works through a web of

cross-talk and

signaling among a variety of cells. One of the first immune

cells that invading

bacteria or cancer cells - both of which carry antigens that alert

the immune system - may

encounter is a natural killer (NK) cell. As its name

implies, NK cells deliver a

deadly blow by poking holes in the invader's outer

membrane. Then, NK cells secrete molecules that reach other immune

cells, including dendritic cells, known as the main messenger for

the immune system. Dendritic cells spread " look

here " information about foreign invaders to other immune

cells, but do not actually kill the invaders.

It was while investigating a particular type of dendritic

cell that Housseau

noticed the outer membranes of these cells were studded

with what were

supposed to be hallmarks of NK cells, akin to finding

feathers on a dog.

" We thought we were looking at dendritic cells, but we were

wrong - they were

some type of NK-dendritic cell blend, " says Housseau. The

blended cell

turned out to be a newly identified actor on the immune

system stage that retains

all the molecular characteristics of both NK and dendritic

cells.

Probing further, Housseau scoured the surface of IKDCs to

create a sketch of

its molecular profile. He found that it produces both types

of interferon

proteins, normally secreted independently by NK and

dendritic cells. He also

found both NK and dendriticlike molecules on the surface of

IKDCs. Housseau

calculated that they account for about 10 percent of

conventional dendritic

cells in the spleen.

IKDCs begin their lives behaving like an NK cell. After the

cell encounters a

pathogen, the cell switches roles from killer to

dendriticlike messenger,

and, according to the researchers, the swap occurs only

once. Then, the cell

dies and is replenished by the bone marrow.

" When an IKDC cell switches to its messenger function, the

transformation is

quite astonishing, " says Pardoll. The cell sprouts long,

hairy tentacles

called dendrites. It uses its " arms " to increase the

amount of surface area it

reaches to communicate and interact with other immune

cells.

In the next step of their investigation, the scientists

tracked the location

of fluorescent-tagged IKDCs and their corresponding stage

of transformation

after infecting mice with bacteria called listeria. In

assassin-mode, the

IKDCs were found in the blood, lining of the gut, liver

and other organs - all

areas where there is close contact with environmental

pathogens. " Here, IKDCs

are ready to sense invaders and spring into action, " says

Housseau.

Then, the group tracked the cells to the main messenger

center of the immune

system - the lymph nodes. Here, they found approximately 35

percent of the

original group of IKDCs now secreting communication

molecules signaling a

switch to messenger-mode.

Simultaneously, Housseau's colleagues in France, led by

ce Zitvogel at

the Institut Gustave Roussy, tested whether IKDCs are

culprits in killing

cancer by injecting mice with a cancer drug called

Gleevec, which blocks an

abnormal protein produced by cancer cells, and a growth

factor for NK cells. The

drug-growth factor combo served as a lure, leading the

IKDCs to tumors

implanted in the mice. The results were that tumors shrunk

in mice, which received

injections of IKDCs, but not in those receiving

conventional NK cells only.

Evidence from the shrunken tumors revealed certain

" cell-killing " proteins that could be traced to IKDCs. These results

are published separately in Nature Medicine.

Housseau's group is conducting further studies to verify

the role of IKDC cells in infection and cancer. Meanwhile, the group

is profiling IKDC genes to find a specific marker that could help

them identify a human counterpart.