Improved Manipulation of "Eat Me" and "Don't Eat Me" Markers in the Context of Cancer

One of the more interesting discoveries of the past few decades in cancer research has been the identity of surface markers such as CD47 that normally act to protect important cells from being attacked and destroyed by immune cells - a "don't eat me" signal. Cancers abuse such mechanisms in a variety of ways, both directly, in cancerous cells, and indirectly, via subversion of regulatory immune cells that are protected by such surface markers, in order to suppress the immune response to the cancer. Targeting CD47 has proven a promising approach to the treatment of cancer, but it has side-effects. There are always necessary cells in the body that should be protected in this way, but that become casualties as a result of treatment.

For decades, researchers have known that the immune system not only plays a key role in battling cancers through the direct action of killer T cells and other components, but also opposes these efforts through cells known as regulatory T cells (Tregs). These Tregs help to regulate the immune response by preventing various immune cells from becoming overactive and causing autoimmune diseases. However, they also accumulate in tumors, shielding them from immune attack.

Tregs maintain a balance of two proteins on their surfaces - CTLA-4 and CD47 - that respectively broadcast "eat me" and "don't eat me" signals to phagocytes that keep Tregs in check. Various immunotherapies have sought to boost the "eat me" signal or decrease the "don't eat me signal" to reduce Tregs in tumors. However, each strategy has drawbacks: Increasing the "eat me" signal has systemic effects that spur autoimmunity, while decreasing the "don't eat me" signal has only shown promise for treating blood cancers, such as leukemias.

Searching for a new way to deplete Tregs, researchers created a two-arm molecule that simultaneously increases the "eat me" signal while blocking the "don't eat me" signal to prompt phagocytes to consume those immune suppressive cells. When it was injected into mouse models of colon cancer, they found that it preferentially depleted Tregs in tumors without affecting those in the rest of the body, sparing the animals from treatment-induced autoimmune disease. However, dosing these animals with equivalent, separate amounts of the "eat me" booster and "don't eat me" blocker had systemic autoimmune side effects, suggesting that combining them within one molecule is key to reaching Tregs in tumors. As the number of Tregs decreased with treatment, the animals' tumors shrank significantly. This strategy also worked in mice carrying human lung cancer tumors, suggesting that it could be viable in human patients.