October 23, 2007

Unmasking and killing resistant tumors
Scientists at RIKEN improve an experimental therapy that harnesses the immunesystem to circumvent tumor resistanceIn the battle against cancer, much attention has been directed at ways to help the body's
own immune system recognize, reject and kill tumors. Unfortunately, progress has been
impeded by the inherent complexity of the immune system.
Now, scientists from RIKEN's Research Center for Allergy and Immunology, led byShin-ichiro Fujii, in collaboration with the Laboratory of Cellular Physiology andImmunology at Rockefeller University in New York, describe a strategy in the Journal ofExperimental Medicine, that could help to significantly advance cancer vaccines, which
are the focus of increasing interest in the field of cancer immunotherapy.
Cancer immunotherapy takes advantage of one of the immune system's natural roles:
detecting and killing precancerous cells. Of the many cell types comprising the immune
system, the highly specialized dendritic cells (DCs) have recently taken center stage,
especially in the emerging arena of cancer vaccines. The RIKEN team collaborated onthis research with eminent Rockefeller University researcher Ralph Steinman, whodiscovered DCs. These cells are the key orchestrators of an activated immuneresponse, which involves 'killer' T-cells (TKs) and other players working in concert tomarshal appropriate defenses against threats within the body.
Early in the immune response, the DCs engulf and break up foreign organisms orunwanted self-cells before presenting the processed portions of the target, or antigens,to the TKs, thereby priming these killer cells to identify and attack the targets. During theintimate and elaborate 'embrace' underpinning this antigen presenting process, the cells
exchange critical information using specific proteins on their surfaces as part of a highly
sensitive system of checks and balances.
Many malignant tumors escape immune attack by capitalizing on this rigorous
regulation to instill, in key effectors, a form of 'tolerance.' Such tumors have evolved
elaborate mechanisms of subterfuge that routinely flummox what is otherwise a highlysophisticated and effective system of immunity.

Fujii's group developed a cancer vaccine that, in effect, turns off the braking signals
deployed by such resistant tumors. The main challenge with cancer vaccines has beenfinding effective cancer-associated antigens - often a frustrating hit-and-miss process that can be appropriately packaged to induce sufficiently strong and persistentanti-tumor immune responses. To address this, the scientists utilized whole tumor cells
coated with alpha-galactosylceramide (AGC) - a chemical glycolipid that specifically
activates very specialized killer cells called NKTs - to create a potent new type ofvaccine. The researchers demonstrated that mice administered this specialized vaccine
were protected from four different types of lethal tumors.
The scientists injected single loads of one type of AGC-modified tumor cells,
intravenously, into mice that were then inoculated, several weeks later, under the skin,with active tumor cells. Unvaccinated mice succumbed rapidly to these aggressive
tumors but vaccinated mice not only survived but their resistance to these tumors also
persisted for 6-12 months, an eternity for such short-lived animals. The same results
were duplicated using three other tumor cell types.
Moreover, in contrast with other methods, this effective strategy utilized a low load oftumor cells, a critical safety consideration in cancer vaccines. This vaccine's potency
hinges on NKTs and the capture and presentation of AGC by DCs: NKTs rejected theAGC-loaded tumor cells, setting off a complex cascade of stimulatory signals anchoredand mobilized by several subsets of DCs, culminating in long-term T-cell based
immunity.
Because AGC seems to be safely tolerated in patients, and since AGC-coated tumor
cells first killed by irradiation were also effective in immunizing mice, Fujii and hiscolleagues believe that clinical trials using this approach can be safely attempted toidentify the most effective tumor cell types that can override tumor tolerance. Suchcancer vaccines may soon be added to our arsenal against cancer.
Original work:
Shimizu, K., Kurosawa, Y., Taniguchi, M., Steinman, R. and Fujii, S. Cross-presentationof glycolipid from tumor cells loaded with galactosylceramide leads to potent andlong-lived T cell-mediated immunity via dendritic cells. The Journal of Experimental
Medicine, published online on Oct. 19, 2007.

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