One way tumors fly under the radar of the immune system is by using IDO, an enzyme used by fetuses to help avoid rejection, to recruit powerful regulatory T cells that turn down the immune response, researchers say.
It was known tumors assemble a protective barrier of regulatory T cells, or Tregs, but how they are such able recruiters was an unknown, says Dr. David Munn, pediatric hematologist/oncologist at the Medical College of Georgia Cancer Center.
"People have been very interested in how the tumor gets so many of these cells and how they get activated so they tend to be very aggressive, more suppressive in the tumor than they appear to be elsewhere in the body," Dr. Munn says of Tregs, major players in preventing autoimmune diseases such as arthritis and type 1 diabetes, where the immune system attacks body tissue.
Research published online Aug. 16 in The Journal of Clinical Investigation shows IDO, which seems to play a powerful role in tumor survival despite the relatively few number of cells in the tumor's draining lymph nodes, directly activates existing Tregs which become strongly suppressive within a day. "The number doesn't change a lot, but their activation state changes hugely," says Dr. Munn, corresponding author.
Studies in a tumor animal model show this rapid conversion occurs only in lymph nodes connected to tumors.
The findings further define a tumor's survival strategy of first recruiting IDO, which helps recruit Tregs. Tregs then up-regulate the PD-L1/PD-L2 pathway, which has been shown to play an important role in the immune suppression caused by AIDS.
"For the first time it creates a link between IDO, regulatory T cells and this novel pathway we don't know much about," says Dr. Munn. Interestingly it's a link that appears to come full circle because, as researchers at the University of Perugia in Italy showed in 2003, in the test tube at least, Tregs also help recruit more IDO.
"IDO appears to be a sort of linchpin; it's a crossroads where a number of mechanisms, some of which are more powerful than IDO itself, come together," says Dr. Munn. "Tregs, for example, are much more powerful than IDO. If you take a mouse and remove IDO, it compensates just fine. If you remove Tregs, the mouse dies. But if the tumor uses IDO to recruit and activate Tregs, that is a leverage point."
Therapies aimed at these new leverage points will be most effective when packaged with other emerging and existing treatments, he says.
The FDA has approved early clinical trials of the IDO inhibitor, 1MT, in coming months. A team, led by longtime collaborator Dr. Scott Antonia, hematologist/oncologist and co-leader of the Immunology Program at the H. Lee Moffitt Cancer Center and Research Institute, will begin phase 1 trials of 1MT in patients with lung and other tumors shortly. MCG is pursuing FDA approval to begin trials of the combination of 1MT and chemotherapy in breast cancer patients. Dr. Munn notes that while the IDO inhibitor seems to be a safe drug that doesn't cause autoimmune disorders in mice, it won't be used in patients with autoimmune disorders because it could worsen the disorders.
By combining IDO with chemotherapy, researchers hope to "Wipe the slate clean" of the tumor's manipulation of the immune response, says Dr. Munn. "We have found that once the tumor gets a hold of the immune system, just giving an IDO inhibitor does not restore everything to normal. The tumor has too much influence on the immune system at that point."
Standard doses of chemotherapy reduce immune system function, creating a window where IDO likely can be more effective. That window may work for cancer vaccines too, which are still under study and getting mixed reviews. Recent reports indicate vaccines can actually increase the number of Tregs in mice with tumors, a problem when fighting cancer but a possible opportunity in which an IDO inhibitor might improve efficacy, Dr. Munn says. An antibody to the PD-L1/PD-L2 already under study in cancer may be another component of a total anti-tumor package.