Like a parasite exploiting its host, some tumors protect themselves by recruiting non-tumor cells that normally help keep the immune system in check, say researchers at the Medical College of Georgia.
When the researchers looked into the lymph nodes where tumors drain – typically the first place tumors spread – they found a subset of normal host immune cells were expressing IDO, an immunosuppressive enzyme also expressed by the fetus to help avoid rejection by the mother's immune system.
They also found that when they gave a drug to block IDO expression, the immune system rallied.
"Our hypothesis in this situation was that the bad guys in this case were actually cells from the host, perfectly normal cells that had, in a sense, been requested by the tumor," says Dr. David Munn, pediatric hematologist-oncologist and lead author on the study published in the July 15 issue of Journal of Clinical Investigation.
Now they have shown in an animal model that these normal cells are a type of dendritic cell that was previously ignored by the scientists because they believed the cells were involved in making antibodies not in suppressing the immune system. By recognizing the actual role of these previously discarded cells, the MCG scientists and their collaborators have moved significantly closer to using this approach to help cancer patients.
"We have demonstrated that the IDO inhibitor drug is useful in mice," says Dr. Munn. "It's useful in a tumor model that is related to the kinds of patients we would want to treat. This brings us closer to being able to approach the FDA suggesting that IDO inhibitor drugs would be appropriate to use in patients."
The National Institutes of Health will do toxicity studies of the IDO inhibitor as well as other studies needed to take the proposal for clinical trials to the Food and Drug Administration, Dr. Munn says.
Should the FDA move toward clinical trials, it likely will be at least a year before studies begin to look at the safety and efficacy of the treatments that would help make tumors more vulnerable to the immune system, Dr. Munn says. He added that the therapy likely would be an adjunct to existing approaches such as chemotherapy and possibly a tumor vaccine that stimulates the immune response.
"It's a general property of any tumor that survives long enough to come to medical attention that it has figured out a way to evade the immune system," Dr. Munn says. "What we would hope is that some group of tumors would rely primarily on this IDO mechanism to do that. It may not be because they are a particular type of tumor. It may be that tumors try different mechanisms and some breast cancers, colon cancers, melanomas or whatever hit on this particular strategy."
The idea of using this strategy against tumors began in 1998 when MCG scientists reported in Science that the fetus used IDO – indoleamine 2,3-dioxygenase – to locally disable the mother's immune system and avoid rejection. The potential of using the IDO mechanism to manipulate immune response is being explored in other areas as well, such as protecting transplanted organs from rejection and helping the immune system fight HIV infection.
Fortunately, several compounds that might inhibit IDO already existed, developed as part of studying pathways involving the natural amino acid, tryptophan. Tryptophan is a precursor to the neurotransmitter, serotonin, and some popular antidepressants work by making serotonin more available to the brain. IDO suppresses the immune response by degrading tryptophan, which also is important to T cells, major orchestrators of the immune response.
The MCG researchers were able to identify and isolate the IDO-expressing cells recruited by the tumor by using state-of-the-art cell-sorting equipment purchased for MCG by the Georgia Research Alliance. "Once we had them isolated, that allowed us to test them in vitro to see if they really were suppressive like we thought," Dr. Munn says. "Then, the most convincing part of this to us was that we could transfer the cells from a mouse that had a tumor into another that didn't and see if the immune system of the tumor-free mouse also became suppressed. And the answer was, 'Yes it did.'"
While he is excited about the potential of using the laboratory findings to help patients, Dr. Munn says the steps from bench to bedside are still complex. In the last few years, scientists have recognized that the immune system is not a passive observer. Rather, there are ongoing natural mechanisms, including IDO expression, that actively help keep the immune system tolerant. "We have to be tolerant of ourselves all the time; otherwise, you get autoimmune diseases such as arthritis and lupus," Dr. Munn says. "It's the difference between a car that is sitting there not moving but doesn't have on the emergency brake so it could move versus one that has on the emergency brake and can't move until you take it off. Natural tolerance mechanisms are like a brake that must be removed before the immune system will attack the tumor.
"If you take off the brakes (for example with an IDO inhibitor drug), you may make people sick. We need to be very careful that we do not do something that causes harm to patients. So that is our next task: to test it in animal models to see if it's a safe and appropriate thing to give patients," Dr. Munn says.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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