Reagent under study as cancer vaccine may also help protect tumors

A bacterial mimic under study as a cancer vaccine because it signals the immune system to attack may also help some tumors hide, researchers have found.

Inside the body, the reagent - CpG oligodeoxynucleotides or CpG-ODNs - alerts the body's natural warning system to an invader, says Dr. Andrew L. Mellor, immunologist and director of the Medical College of Georgia Immunotherapy Center.

In an animal model, Dr. Mellor and his colleagues have found CpG-ODNs also can trigger a mechanism that may have helped the tumor survive in the first place: expression of an enzyme that enables it to hide from the immune system.

"What we have found is the ability to ring the alarm bell is a double-edged sword," says Dr. Mellor of new findings reported as a Cutting Edge article in the Nov. 1 issue of The Journal of Immunology. "The immunology community believes that the only thing these bacterial mimics do through the Toll-like receptors is ring the alarm bells to stimulate T cells to action. We are saying that if you deliver them in a certain way, they will also signal induction of the mechanism we have been working on which does exactly the opposite."

The mechanism is an enzyme, indoleomine 2,3-dioxegenase, that locally suppresses the immune response. MCG researchers reported in Science in 1998 that one way fetuses avoid rejection by the mother's immune system is expressing IDO, which degrades tryptophan, an amino acid essential to survival of T-cells, orchestrators of immune response. Since then, the researchers have found that tumors and some infectious agents, such as HIV, use this mechanism to escape the immune system.

In fact, Dr. David Munn, pediatric hematologist-oncologist, study co-author and Dr. Mellor's longtime research partner, is working with the National Institutes of Health on toxicity studies of an IDO inhibitor the researchers use in the lab with the goal of moving toward clinical studies of its potential to help cancer patients fight resistant tumors.

Dr. Munn says the treatment would likely be an adjunct to existing treatments, such as chemotherapy. Their newest study indicates the IDO inhibitor may also be a good companion treatment for the cancer vaccine that utilizes CpG-ODNs, says Dr. Mellor, a Georgia Research Alliance Eminent Scholar in Molecular Immunogentics.

CpG-ODNs work by binding to Toll-like receptors, found on a number of different immune cells, including the pervasive dendritic cells that direct T cells. "About a decade ago, it was discovered that what these Toll-like receptors have evolved to do is recognize what we immunologists call danger," says Dr. Mellor. "Danger comes in many forms, but the way to think about this is that bacteria and pathogens will produce new structures which are seen as dangerous by the immune system using these receptors. This is absolutely the way you should respond to danger. You should get the T cells involved."

But the double-edged sword comes in because some dendritic cells also can express IDO and turn T cells off, the MCG researchers say.

One of the many directions their research is taking is exploring the role of IDO in regulatory T cells, that also have the ability to shut down the immune response, ideally to keep it from attacking the body's own tissue in autoimmune diseases such as arthritis.

"Regulatory T cells are really important to consider in many disease situations," says Dr. Mellor. "In the context of cancer, it's known that tumors induce regulatory T cells, which is in the interest of the tumor, not the patient. The patient wants to get rid of regulatory T cells in this circumstance because they are not helping the immune system to destroy the tumor. IDO is working in the same direction: it's helping to protect the tumor from attack."

One of their questions is whether IDO is helping generate regulatory T cells.

If the answer turns out to be yes, it will provide evidence that IDO is not just one way tumors protect themselves, but an essential factor in this unfortunate ability, Dr. Mellor says.

Co-authors on the current study include Dr. Munn; Dr. Phillip R. Chandler, principal research scientist, MCG Immunotherapy Center; Dr. Babak Baban, research scientist, MCG Immunotherapy Center; and Anna Manlapat and David J. Kahler, graduate students in Dr. Mellor's lab.