Improving Efforts to Bypass the CD47 "Don't Eat Me" Marker Employed by Cancers

Cancers evolve to hide from or co-opt the immune system in a range of ways, some more successfully than others. Since one of the primary tasks of the immune system is to destroy cancerous cells, all cancers must defeat immune surveillance mechanisms to at least some degree. One strategy common to a large faction of cancers is use of CD47, a cell surface feature that the immune cells called macrophages treat as a "don't eat me" signal. In recent years researchers have made considerable progress on a range of ways to interfere with CD47 recognition in macrophages, freeing them to attack cancerous cells with vigor. This latest work builds on that foundation, improving the understanding of the underlying processes, and introducing a new way to take best advantage of sabotage of the CD47 mechanism.

Macrophages are immune cells just like T cells and B cells, but differ in that they can eat cells that are not supposed to be in the body. In fact, they are the most prominent immune cell found in cancer, but unfortunately, most are often convinced to help cancer grow and spread. Cancer cells frequently stop macrophages from attacking them by expressing CD47, a "don't eat me" signal. Researchers now say that merely blocking inhibitory signals like CD47 is not always sufficient to convince macrophages to attack cancer. Instead, two signals are required. First, they need a signal to activate them - such as a toll-like receptor agonist. After that, a second signal - such as a CD47 inhibitor - can lower the threshold needed to wage battle on the cancer.

The team used this approach by activating macrophages with CpG, a toll-like receptor agonist that sends the first signal, and found that it rapidly induced shrinkage of tumors and prolonged survival of mice even without the requirement of T cells. Unexpectedly, they also found that the activated macrophages were able to eat cancer cells even in the presence of high levels of CD47.

To understand the molecular basis of this phenomenon, the team traced the metabolic activity of macrophages and determined that activated macrophages began to utilize both glutamine and glucose as fuel to support the energy requirements needed for them to eat cancer cells. This rewiring of the macrophages metabolism was necessary for CpG to be effective, and the researchers say these findings point to the importance of macrophage metabolism in determining the outcome of an immune response. "It is the metabolism that ultimately allows macrophages to override signals telling them not to do their job."