November 27, 2017, New York — Ludwig Stanford researchers led by Irv Weissman, Director of the Ludwig Center at Stanford, have discovered a second biological pathway that stops immune cells called macrophages from engulfing and killing cancer cells.
The known mechanism by which cancer cells disable macrophage attack—also reported by Weissman’s lab in 2009—involves a protein known as CD47 that is expressed on the surface of most cancer cells. Blocking that signal with anti-CD47 antibodies induces a dramatic regression of tumors in animal models, and the strategy is currently being evaluated in early stage clinical trials. Weissman and his colleagues describe in the current issue of Nature Immunology an additional “don’t eat me” signal and demonstrate that blocking both CD47 and the newly discovered signal results in the infiltration of tumors with many types of immune cells and significantly promotes the clearance of tumors in an animal model.
Macrophages engulf and kill invaders, like bacteria and viruses, and can similarly attack malignant cells. The newly discovered “don’t eat me” signal employed by macrophages capitalizes on a protein complex found on the surface of most cells called the major histocompatibility complex class 1, or MHC class 1. This complex displays bits of proteins found within a cell, providing a sort of window into its health. If the bits appear foreign or abnormal, immune cells known as T cells destroy the presenting cell. Although the relationship between MHC class 1 and T cells is well-established, it has long been unclear whether and how the complex interacts with macrophages.
Weissman and his team found that human tumors that express high levels of MHC class 1 are more resistant to anti-CD47 treatment than are those with lower levels of the complex. This, they show, is because a protein called LILRB1 on macrophages binds to a portion of MHC class 1 and inhibits the ability of macrophages to engulf and kill the cancer cells.
Cancer cells often reduce MHC class 1 expression to escape destruction by T cells, and people with these types of tumors may not respond to cancer immunotherapies that stimulate T cell activity. 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, but might be susceptible to LILRB1 inhibition.
“These findings help us understand the many ways cancer cells can evade macrophages, and how we might block these escape pathways,” says Weissman.
The original release on which this summary is based can be found here.