No, it's not a plea from the leftover Thanksgiving turkey you may have just gobbled (see what I just did there?). A "don't eat me" signal on cancer cells was identified in 2009 by researchers in the laboratory of stem cell expert Irving Weissman, MD. It serves to keep immune scavengers called macrophages (shown at right) from engulfing and destroying the rogue cells. An antibody that blocks this signal, known as anti-CD47, is currently in phase-1 clinical trials in people with a variety of blood and solid tumors.
Now the same group, including graduate student Amira Barkal and former graduate student Kipp Weiskopf, MD, PhD, has identified another similar but distinct pathway that protects cancer cells from macrophages. Blocking both pathways simultaneously may further enhance the immune system's ability to seek out and destroy tumors, they believe. They published their results in Nature Immunology.
As Weissman explained in our release:
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.
Macrophages are part of what's known as our innate immune system, which patrols the body routinely looking for all kinds of trouble in the form of invading bacteria or viruses, or dead or dying cells that need to be removed. They also can attack and destroy some cancers.
In contrast, MHC class 1 works to activate a more-specialized immune response called adaptive immunity. In adaptive immunity, immune cells like T cells and B cells are alerted by other cells to swiftly respond to specific threats. 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.
The new research shows that a protein on the surface of the macrophages called LILRB1 binds to a portion of the MHC class 1 structure that is widely shared across individuals. As in the CD47 pathway, this binding helps to keep macrophages from engulfing the cells. Inhibiting the binding between LILRB1 and MHC class 1 significantly slowed tumor growth in mice, the researchers found.
From our release:
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.
Weissman is the director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, and also of its Ludwig Cancer for Cancer Stem Cell Research and Medicine. He explained, “In some cancers, MHC class 1 expression, for a variety of reasons, is not reduced, and this helps the cancer cells escape from macrophages. These findings help us understand the many ways cancer cells can evade macrophages, and how we might block these escape pathways.”
Previously: Single antibody shrinks or eliminates human tumors in mice at Stanford, Cancer uses inflammatory pathways to protect itself and Immunotherapy may help treat kids' brain tumors, preliminary Stanford study shows
Image by NIAID