Dendritic cells - a part of the body's immune system that detects foreign proteins in the body - can be used as vaccines by mixing them with genetic material from the patient's tumour and infusing the treated cells back into the patient. The dendritic cells present the tumour antigens to the body's white blood cells (T lymphocytes) for destruction.
However, it was found that dendritic cell vaccines failed to remove the regulatory T cells that restrain excessive or unwarranted T cell aggression. Releasing the fighter T cells would allow them to attack the cancer. Yet removing all restraints could provoke T cells to attack the body indiscriminately, potentially causing autoimmune reactions.
The findings, published in the April 4, 2004, issue of Nature Immunology raise hopes of an eventual vaccine which could be used as protection from various forms of cancer.
Dr Yiping Yang, assistant professor of medicine and immunology, the lead author and principal investigator of the study said: "Dendritic cell vaccines have shown promise in battling cancers in laboratory studies, but they have not met with quite the success in the clinical trials that laboratory studies suggest they should."
Cancer cells cause difficulty when creating a vaccine because they are in essence part of the host's living tissue. This makes it difficult for the immune system to recognise them. Dendritic cells present the tumour antigen to T cells, yet T cells tolerate the antigen and mount no response.
The team discovered viral vaccines naturally override these cellular brakes, as viruses contain their own unique and foreign molecules that mark them as invaders in the body. These are known as "pathogen-associated molecule patterns" (PAMPs), and are unique to viruses, bacteria and other pathogens.
Yang stated: "They reside on the coating of the bacterium or virus and are separate and apart from the cancer antigen."
"When the viral vaccine presents the tumour antigen to fighter T-cells (via the patient's dendritic cells), it is also presenting its own PAMPs. The dual signalling provides the needed stimulus to energise T cells into action."
"Dendritic cells are viewed by the body as self - even when they are loaded with tumour antigen - because the antigen itself is not enough to provoke fighter T cells to act," said Yang.
"If you mix dendritic cells with tumour antigen and PAMPs, then you produce a more potent signal that can break T cell tolerance."
The team identified the site on the surface of dendritic cells that recognizes the PAMPs and prompts them to silence regulatory T cells. The sites are called Toll-like receptors, and activating them is critical to temporarily silencing regulatory T cells.
"We don't know the specific chain of events that Toll-like receptors activate inside dendritic cells to temporarily silence regulatory T-cells," said Yang. "But we hypothesise that signals enter through the Toll-like receptors and trigger the release of critical cytokines that tell regulatory T cells to lie dormant."
Viral vaccines naturally accomplish this task on their own, yet they present their own complex array of limitations. Viral vaccines must be created with the precise strands of tumour DNA (called specific-specific antigens) that will spark recognition among the fighter T cells.
However, the tumour-specific antigens for most cancers are unknown, and finding them can be extraordinarily time-consuming and costly. In contrast, dendritic cells can be laced with tumour proteins or RNA that already contain tumour-specific antigens - a much easier task than isolating the antigens. Second, viral vaccines must be stripped of their potential to cause illness in the patient.
Yang said: "We want to merge the strengths of viral vaccines with the ease of using a patient's own immune system to wage war against the cancer."
Yang and his team have tested the concept successfully in animals and plan to test the viral vaccines and the dendritic cell vaccines in lymphoma patients within the next several years.