Cancer can often evade the immune system by sending signals that fool it into thinking that the cancer cells are normal, healthy cells and that it should ignore them. Earlier this year, we reported on an approach to treating cancer in which the immune system can be taught to detect cancer by seeing past the cancer cell’s attempts to hide.
One of these attempts involves a signaling pathway that sends a “don’t Eat Me” signal to the immune system. Now, researchers at the Stanford University School of Medicine have discovered a second biological pathway that signals the immune system not to engulf and consume cancer cells.
A second path unmasking cancer
An antibody that blocks the “don’t eat me” signal has shown promise as a cancer treatment in animal tests and is now in human clinical trials. Combining this antibody, known as anti-CD47, with another that blocks this new pathway could further boost the ability of the immune system to eradicate multiple types of cancer.
When cancer cells develop, this sends an alarm signal that summons macrophages to attack and destroy the cells. However, aggressive forms of cancer often express this “do not eat me” signal in the form of CD47 on their cell surfaces, which keeps the immune system at bay. The researchers in this new study have found that they can overcome this signal using specific antibodies that allow the macrophages to detect and destroy the cancer cells.
The researchers believe that blocking both pathways would be an effective strategy for combating cancer; in mice, doing this resulted in infiltration of tumors by various types of immune cells and promoted tumor clearance. The researchers are very interested in exploring this double-pathway approach and are even interested in potentially adding other pathways to the target list to make it even more effective.
Macrophages are part of the innate immune system, and their job is to engulf and destroy invaders, such as bacteria or viruses. Macrophages also clear away dead and dying cells as well as cancer cells when they are able to detect them.
The original “Do not eat me” signal was originally identified back in 2009 at Weissman’s laboratory in two studies, in which researchers discovered that the majority of cancer cells strongly express CD47 on their surfaces[2-3]. At the time, the research team demonstrated that CD47 binds to signal-regulatory protein alpha (SIRPalpha), which is present on the surfaces of macrophages, blocking their ability to identify and destroy cancer cells.
The follow-up mouse studies showed that therapy with anti-CD47 antibodies boosted the ability of macrophages to spot and kill cancer cells and, in some cases, even led to a cure. There are currently phase 1 clinical trials underway at Stanford and in the U.K. to see if the approach is safe to use in humans.
Calling in the macrophages
The new study has discovered that cancer cells have a protein structure on their surfaces known as major histocompatibility complex class 1, or MHC class 1, in order to evade macrophages via a binding interaction. Tumors that have more MHC class 1 on their surfaces are more resistant to anti-CD47 therapy than those with less.
MHC class 1 is part of the adaptive immune system, which uses immune cells, including T cells and B cells, to respond to microbial invaders and damaged cells. Most cells in our bodies express MHC class 1 on their surfaces as a means of showing a range of protein bits found within the cell; it acts almost like a window into the cell providing information on the cell’s health. If the protein bits (peptides) being shown by the MHC are not that of a healthy cell, the T cells will detect this and destroy the unhealthy cell. The relationship between MHC Class 1 and T cells is well known, but it was unclear how MHC Class 1 and macrophages interacted until now.
The new study shows that a protein called LILRB1, which is present on the surface of macrophages, binds to part of the MHC class 1 on cancer cells; this binding then prevents the macrophage from engulfing the cancer cell and destroying it. This has been observed both in cell culture tests and in mice with human cell tumors. The researchers discovered that inhibiting CD47 and LILRB1 pathways slowed tumor growth significantly in mice.
Using a two-pronged approach and targeting two pathways at once could prove effective. Some cancer cells can reduce the expression of MHC class 1 on their surfaces to evade destruction from T cells; thus, people with tumors will not respond to therapies that stimulate T cell populations against cancer. However, the cancer cells that reduce their MHC class 1 in this manner are likely to be vulnerable to anti-CD47 therapies. The opposite is also likely true; cancer cells that express more MHC class 1 on their surfaces will be much more resistant to anti-CD47 therapy.
This study is interesting and builds on our knowledge of how cancer evades our immune system and adds to the arsenal of weapons that we can use to defeat it. Immunotherapy holds huge potential in the war on cancer, and so we are watching further developments closely.
 Barkal, A., Weiskopf, K., … & Weissman, I. L. (2017) Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nature, doi:10.1038/s41590-017-0004-z
 Majeti, R., Chao, M. P., Alizadeh, A. A., Pang, W. W., Jaiswal, S., Gibbs, K. D., … & Weissman, I. L. (2009). CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell, 138(2), 286-299.
 Jaiswal, S., Jamieson, C. H., Pang, W. W., Park, C. Y., Chao, M. P., Majeti, R., … & Weissman, I. L. (2009). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell, 138(2), 271-285.