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November 28, 2017

Discovery of Second “Don’t Eat Me” Signal May Lead to Tighter Cancer Immunotherapy

  • Cancer cells aren’t content with just one signaling mechanism to evade the innate immune system. No, in addition to a “plan A,” a surface molecule called CD47, cancer cells have a “plan B,” a surface molecule called LILRB1, or leukocyte immunoglobulin-like receptor B1. Both the CD47 pathway, which was discovered several years ago, and the LILRB1 pathway, which has been identified in a new study, give macrophages a clear message: “Don’t eat me.” Shutting down both pathways could improve anticancer immunotherapy by putting ever-elusive cancer cells back on the macrophage menu.

    Both pathways were discovered in the laboratory of Irving Weissman, M.D., the director of Stanford University's Institute for Stem Cell Biology and Regenerative Medicine and also of its Ludwig Cancer Center.

    In 2009, Weissman and colleagues found that nearly all cancer cells express high levels of CD47 on their surfaces. The scientists showed that CD47 binds to a protein called SIRPα, or signal regulatory protein α, on the surface of macrophages, inhibiting their ability to kill the cancer cells.

    Animal studies showed that treatment with an anti-CD47 antibody vastly improved the ability of macrophages to kill cancer cells and even led to some cures in mouse models of cancer. Phase I clinical trials are currently underway at Stanford and in the United Kingdom to test the safety and efficacy of the treatment in humans with a variety of blood and solid tumors.

    The newly discovered binding interaction, the LILRB1 pathway, capitalizes on a protein structure on the cancer cells' surface called the major histocompatibility complex class I, or MHC class I. Human tumors that have high levels of MHC class I on their surfaces are more resistant to anti-CD47 treatment than are those with lower levels of the complex, the researchers found.

    Additional details appeared November 27 in the journal Nature Immunology, in an article entitled  “Engagement of MHC Class I by the Inhibitory Receptor LILRB1 Suppresses Macrophages and Is a Target of Cancer Immunotherapy.” The article describes how cancer cells that express the common MHC class I component β2-microglobulin (β2M) avoid being engulfed by macrophages. This avoidance mechanism, the article’s authors indicated, is mediated by LILRB1, an inhibitory receptor whose expression is upregulated on the surface of macrophages, including tumor-associated macrophages.

    “Disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo,” wrote the article’s authors. This finding, the authors continued, “defines the MHC class I–LILRB1 signaling axis as an important regulator of the effector function of innate immune cells, a potential biomarker for therapeutic response to agents directed against the signal-regulatory protein CD47 and a potential target of anti-cancer immunotherapy.”

    "The development of cancer cells triggers the generation of SOS molecules recognized by the body's scavenger cells, called macrophages," explained Dr. Weissman, the co-senior author of the Nature Immunology article. "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," added graduate student Amira Barkal, a co-author of the current paper. "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."

    MHC class I is an important component of adaptive immunity, the second major arm of the immune system, which relies on immune cells called T cells and B cells to nimbly and specifically respond to foreign invaders and cell damage. Most cells of the body express MHC class I 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 I and T cells has been well established, it's been unclear whether and how the complex interacts with macrophages.

    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 I 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 I on their surfaces may be less susceptible to anti-CD47.

    "In some cancers, MHC class I expression, for a variety of reasons, is not reduced," Weissman noted, "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."

    "The fact that there are at least two redundant mechanisms to modulate macrophage activity is a testament to how critically important it is to tightly control our immune responses," Barkal said. "It's possible that future studies will identify even more of these pathways, which will give us additional targets for cancer immunotherapy."

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