Cancer’s ability to elude our body’s immune system has long puzzled researchers. The latest study pinpoints one of cancer’s protective cloaks and investigates a way to remove it.

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Cancer and its interaction with the immune system is a complex story.

Cancer cells are cells that have gone awry; they both multiply unchecked and function incorrectly. Normally, cells that are faulty, dead, or dying are cleared away by the immune system.

Macrophages — a type of white blood cell — are largely responsible for the consumption and destruction of foreign invaders and errant cells.

Although macrophages normally carry out their attacks with ruthless efficiency, some cancer cells manage to evade their roaming gaze. How do cancer cells fly under the immune system’s radar?

In 2009, Dr. Irving Weissman, director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, published research that goes some way toward answering this question. They identified a “don’t eat me” signal on cancer cells.

Dr. Weissman demonstrated that particularly aggressive cancer cells express higher levels of CD47 — a transmembrane protein — on their cell surface. CD47 binds to a protein called SIRPalpha on the surface of macrophages, reducing their ability to attack and kill the cancer cells.

Studies in animals have shown that treatment with an anti-CD47 antibody significantly increases macrophages ability to kill cancer cells. In some mouse models of cancer, the treatment even led to a cure. Clinical trials are underway to gauge whether this approach will be as successful in humans.

Recently, Dr. Weissman’s team published another paper, outlining research that uncovers another “don’t eat me” signal. This time, the molecule in focus is a cell surface protein called major histocompatibility complex class 1 (MHC class 1).

The researchers found that tumors with higher levels of MHC class 1 on their cell surfaces are more resilient to anti-CD47 treatment.

Adaptive immunity forms the basis of immunological memory — once our immune system has responded to a specific pathogen, if it meets the same intruder again, it can mount a swift and specific response. MHC class 1 are an important part of this wing of the immune system.

MHC class 1 are found on the surfaces of most cells. They take portions of internal cellular proteins and display them on the cell’s surface, providing a snapshot of the cell’s health. If the cell’s protein flags are abnormal, T cells destroy it. This interaction between MHC class 1 and T cells has been well described, but how macrophages are involved was not fully understood.

The current study found that a protein — LILRB1 — on the surface of macrophages binds to a part of MHC class 1 on the surface of cancer cells. Once it has bound, it prevents the macrophage from consuming and killing the cell. This response was seen both in a laboratory dish and in mice with human tumors.

By inhibiting the CD47-mediated pathway and the LILRB1 pathway, interfering with both “don’t eat me” signals, tumor growth was significantly slowed in mice. The results are published this week in Nature Immunology.

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.”

Amira Barkal, graduate student, joint lead author

Barkal continues, “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.”

Immunotherapy for cancer is a rapidly developing field, but the story is a complex one. Different cancers have different immunological fingerprints; for instance, some human cancer cells reduce the levels of MHC class 1 on their cell surface, helping them to evade T cells.

Individuals with these cancers might not respond particularly well to therapies designed to enhance T cell activity. However, these cancers might be more vulnerable to an anti-CD47 approach. This also works the other way around, cancers with plentiful MHC class 1 might be less affected by anti-CD47 treatment.

Uncovering how cancer cells avoid cell death and understanding how these pathways might be overturned is a difficult but critical endeavor. This study marks another step toward teaching our immune system how to slow cancer’s march.