Apr. 6, 2004 DURHAM, N.C. -- Scientists have discovered why dendritic cell vaccines do not attack cancer as forcefully as expected, and they have demonstrated how to overcome this constraint by bolstering the vaccines' tumor-seeking machinery.
The findings, published in the April 4, 2004, issue of Nature Immunology, present a novel method of equipping dendritic cells so they can activate the immune system to fight against cancers, said the researchers from the Duke Comprehensive Cancer Center and the departments of medicine and immunology at Duke University Medical Center.
Dendritic cells are the "private investigators" of the immune system, detecting foreign proteins in the body -- for example from bacteria and viruses -- and presenting them to "fighter" T-cells for destruction. Scientists turn dendritic cells into cancer vaccines by mixing them with genetic material from the patient's tumor and infusing the treated cells back into the patient. The dendritic cells present the tumor particles – called antigens – to the fighter T cells, as though pointing out the enemy to a battalion of soldiers.
"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," said Yiping Yang, M.D., Ph.D., assistant professor of medicine and immunology, the lead author and principal investigator of the study. "Our study highlights what element is missing in dendritic cell vaccines that prevents them from activating the immune system, and we've shown how to insert that element."
The major problem, said Yang, is that cancer cells are wily invaders, camouflaging themselves as part and parcel of the body in order to escape detection by the immune system. Dendritic cells present the tumor antigen to T-cells, yet T-cells are curiously tolerant to the antigen and fail to act on its threat.
Yang and his team studied why this tolerance occurs by creating an animal model that mimics the same T-cell tolerance that occurs in cancer patients. They compared the behavior of dendritic cell vaccines in the mice against that of viral vaccines, which have their own limitations but seem to engage T-cell aggression without difficulty.
"We knew there was something unique to viral and bacterial pathogens that mammalian cells don't have," said Yang.
The scientists found that dendritic cell vaccines failed to remove the "brakes" from fighter T-cells that would allow them to attack the cancer. These brakes are known as regulatory T-cells, and they restrain excessive or unwarranted T-cell aggression.
Yang and his team theorized that removing the regulatory T-cells would remove the brakes from the fighter T-cells. Yet removing all restraints could provoke T-cells to attack the body indiscriminately, potentially causing auto-immune reactions.
In contrast, viral vaccines naturally override these cellular brakes as needed, and Yang's team determined why that occurs: viruses contain their own unique and foreign molecules that mark them as invaders in the body.
These foreign molecules are known as "pathogen-associated molecule patterns" (PAMPs), and they are unique to viruses, bacteria and other pathogens. They reside on the coating of the bacterium or virus and are separate and apart from the cancer antigen, said Yang. When the viral vaccine presents the tumor antigen to fighter T-cells (via the patient's dendritic cells), it is also presenting its own PAMPs. The dual signaling – in actuality there are three signals from dendritic cells – provide the needed stimulus to energize T cells into action, said Yang.
"Dendritic cells are viewed by the body as self – even when they are loaded with tumor antigen – because the antigen itself is not enough to provoke fighter T cells to act," said Yang. "If you mix dendritic cells with tumor antigen and PAMPs, then you produce a more potent signal that can break T-cell tolerance."
Further, Yang 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 hypothesize 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, said Yang. First, viral vaccines must be laced with the precise strands of tumor DNA (called tumor-specific antigens) that will spark recognition among the fighter T-cells. However, the tumor-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 tumor proteins or RNA that already contain tumor-specific antigens – a much easier task than isolating the antigens, said Yang. Second, viral vaccines must be stripped of their potential to cause illness in the patient.
"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," said Yang.
Thus far, Yang and his team have tested the concept successfully in animals and plan to test the viral vaccines and the bolstered dendritic cell vaccines in lymphoma patients within the next several years.
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