Newly Discovered Killer Cell Fights Cancer

March 3, 2006 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.

"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 Johns 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 Johns 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 Frank Housseau, Ph.D., research associate at Johns 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 Laurence 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.

The Johns Hopkins research was funded by the National Institutes of Health, the Janney Fund and Seraph Foundation, and gifts from Bill and Betty Topecer and Dorothy Needle.

Participants in the research include Camie W. Chan, Emily Crafton, Hong-Ni Fan, James Flook, Kiyoshi Yoshimura, Mario Skarica, and Monique F. Stins from Johns Hopkins; Dirk Brockstedt and Thomas W. Dubensky from Cerus Corporation; and Lewis L. Lanier from the University of California San Francisco.

"Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity" Nature Medicine 12, 167 - 168 (2006).

Video Footage Available: IKDC cell killing a cancer cell. Courtesy of the Institut Gustave Roussy.

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