Cancers evolve to abuse mechanisms that suppress or control the immune system, as any cancer that fails to do so tends to be destroyed early-on by immune cells. One of these mechanisms is the presentation of "don't eat me" signals on the cell surface that prevent macrophage cells of the innate immune system from engulfing and destroying a cancer cell. CD47 was identified some years ago as one of these signals, and bypassing it or suppressing it has the potential to be a broad basis for the treatment of many types of cancer. As a bonus, it also appears to be a potentially viable strategy for treating age-related fibrosis, as the cells that make up fibrotic scar tissue inside aged organs similarly protect themselves with CD47.
Nothing is simple or single-purposed in biochemistry, however. Where there is one signal, there are usually also other overlapping signals that achieve similar or related results. Researchers have now found another, more subtle "don't eat me" signal employed by cancer cells, and as is the case for CD47, this too should have the potential to be useful in a range of future therapies. In fact, the two used together promise to be much better than either on its own, capable of success in more types of cancer.
"The development of cancer cells triggers the generation of SOS molecules recognized by the body's scavenger cells, called macrophages. However, aggressive cancers express a 'don't eat me' signal in the form of CD47 on their surfaces. Now we've identified a second 'don't eat me' signal and its complementary receptor on macrophages. We've also shown that we can overcome this signal with specific antibodies and restore the ability of macrophages to kill the cancer cells. Simultaneously blocking both these pathways in mice resulted in the infiltration of the tumor with many types of immune cells and significantly promoted tumor clearance, resulting in smaller tumors overall. We are excited about the possibility of a double- or perhaps even triple-pronged therapy in humans in which we combine multiple blockades to cancer growth."
Macrophages are large white blood cells found in nearly all the body's tissues. As part of what's known as the innate immune system, they engulf and kill foreign invaders like bacteria or viruses. They also destroy dead and dying cells and, in some cases, cancer cells whose internal development cues have gone haywire. The newly discovered binding interaction used by cancer cells to evade macrophages capitalizes on a protein structure on the cancer cells' surface called the major histocompatibility complex class 1, or MHC class 1. Human tumors that have high levels of MHC class 1 on their surfaces are more resistant to anti-CD47 treatment than are those with lower levels of the complex, the researchers found.
MHC class 1 is an important component of adaptive immunity. Most cells of the body express MHC class 1 on their surfaces as a way to indiscriminately display bits of many proteins found within the cell - a kind of random sampling of a cell's innards that provides a window into its health and function. If the protein bits, called peptides, displayed by the MHC are abnormal, a T cell destroys the cell. Although the relationship between MHC class 1 and T cells has been well-established, it's been unclear whether and how the complex interacts with macrophages.
Researchers found that a protein called LILRB1 on the surface of macrophages binds to a portion of MHC class 1 on cancer cells that is widely shared across individuals. This binding inhibits the ability of macrophages to engulf and kill the cancer cells, both when growing in a laboratory dish and in mice with human tumors, the researchers found. Understanding the balance between adaptive and innate immunity is important in cancer immunotherapy. For example, it's not uncommon for human cancer cells to reduce the levels of MHC class 1 on their surfaces to escape destruction by T cells. People with these types of tumors may be poor candidates for cancer immunotherapies meant to stimulate T cell activity against the cancer. But these cells may then be particularly vulnerable to anti-CD47 treatment, the researchers believe. Conversely, cancer cells with robust MHC class 1 on their surfaces may be less susceptible to anti-CD47.