A way forward: releasing the brakes on cancer vaccines.

Scientists have tried for decades to create vaccines that spur a cancer patient's immune system into attacking tumors, but cancer cells cleverly defuse the attack. Research in mice now suggests a new way to overcome these defenses and rally the immune system to action.

Previous attempts to defeat tumor defenses with a vaccine caused dangerous side effects by provoking the immune system to attack healthy" cells indiscriminately. The new technique is the first with the potential to selectively bolster the immune system's attack on tumor cells while sparing healthy cells.

"This is not like inducing the whole immune response," says Xiao-Tong Song of the Baylor College of Medicine in Houston. Getting an immune response that's specific to tumor cells is difficult, Song explains. Tumors protect themselves by hijacking the immune system's own generic "stop" signals. Simply blocking these stop signals lets the immune system run out of control and attack any cell it finds.

Normally, an intricate balance of stopand-go signals keeps immune cells in check. Some cell types, such as dendritic cells, release go signals while they show the "attack dog" cells characteristic pieces of the cancer cells--much like letting a bloodhound sniff a fugitive's socks. The attack cells should then kill only the cancer cells.

Stop signals released by regulatory T cells (T-regs) calm the attack cells. Unfortunately, tumors recruit and harbor T-regs to placate would-be attackers, so a major goal of cancer-vaccine research has been to stimulate dendritic cells and weaken T-regs.

Song and his colleagues extracted dendritic cells from mouse bone marrow and grew the cells in lab dishes. The researchers revved up these dendritic cells by exposing them to a typical cancer molecule. They also added an engineered virus that blocked the cells from making a protein called A20.

Their results showed that blocking A20 boosted dendritic-cell activity: When the scientists injected the treated cells back into mice with early melanomas, the cells released more go signals than normal. The overactivated attack-dog cells killed tumor cells in spite of the T-regs. Early tumor growth was stymied just as well in mice that had their T-regs reduced. Also, after a month, the mice receiving the treated dendritic cells had no apparent signs of side effects from autoimmunity, the team reports online and in an upcoming Nature Medicine.

The research "provides us with a new understanding of how to manipulate dendritic cells to achieve a more active immune response," comments Louis M. Weiner of the Lombardi Comprehensive Cancer Center at Georgetowna University. in Washington, D.C.