Burning cancer’s bridges to nowhere

If you’ve ever wondered how to resist the pull of a siren’s call, take a lesson from Ulysses’ crew: plug your ears with wax, shutting out the allure of the fatally enchanting song.

In a study published in Cell Reports, Prof. Idit Shachar and her colleagues in the Department of Systems Immunology describe a novel, antibody-based treatment for the most aggressive type of breast cancer that may also combat other cancers. The Shachar group discovered that triple-negative breast cancer bamboozles nearby immune cells into building molecular bridges between themselves, causing these cells to refrain from attacking the tumor and suppressing a useful immune response. An antibody treatment that prevents the formation of these bridges enhances the immune system’s ability to forcibly attack the cancer, inhibiting its progression in a mouse model.

In the past, cancer treatment focused on destroying malignant cells via radiation treatment, chemotherapy, etc. However, in recent decades, researchers have discovered that the development of tumors relies on the interaction between cancer cells and nearby noncancerous cells. A prior study by the Shachar lab revealed that blood cancer cells create molecular bridges with nearby support cells to survive and proliferate—otherwise, they die within days.

The researchers identified a protein, CD84, that is used to construct these bridges: When CD84 is present on the surface of a specific immune cell, it can bind to a similar protein on a different cell, creating an intercellular bridge. The Shachar lab developed an antibody that blocks the bridges in blood cancer, thereby slowing disease progression. Now, the team is collaborating with City of Hope®, a cancer treatment and research center in California, to see if their approach—making the microenvironment less abiding rather than attacking the cancer itself—could aid in countering triple-negative breast cancer.

In the new study, led by Stav Rabani, a PhD student in Prof. Shachar’s lab, the researchers analyzed the genetic sequences of cancerous tissue samples. They discovered that the level of CD84 expression in the tumor microenvironment was much higher than normal. This is surprising: breast cancer cells express very low levels of CD84 themselves; rather, they prompt nearby immune cells to express it in large quantities and to create bridges between themselves, suppressing the immune response. The researchers also found that patients with higher levels of CD84 in their tumors had poorer prognoses.

At the same time, mice that had been genetically engineered not to express the CD84 protein developed significantly smaller cancerous growths. The team then tested their novel antibody—successful against blood cancer bridges—as a treatment for breast cancer. Injections given twice a week to mice that had started developing breast cancer significantly slowed tumor growth and, in some cases, even led to complete recovery.

Furthermore, the scientists demonstrated that when immune cells become distracted and engage in a counterproductive process of building bridges, they also produce a small protein that furthers the cancer’s agenda: When detected by T cells—the immune system’s warrior cells—this protein suppresses their activity and prevents them from attacking the tumor. Burning cancer’s bridges is essential to preventing this self-destructive process.

This novel antibody only works on cells expressing a high level of CD84—not on healthy cells. In an age of personalized medicine, this treatment could help a range of patients, as it focuses on the tumor microenvironment and not on the cancer cells themselves.

Shachar team members (from left): Gil Belisha, Bar Lampert, Bianca Pellegrino, Stav Rabani, Prof. Idit Shachar, Dr. Keren David, Dr. Laura Bellassen, and Dr. Shirly Becker-Herman.

Prof. Idit Shachar is the incumbent of the Dr. Morton & Anne Kleiman Professorial Chair. Her research is supported by the Judy and Bernard Briskin Multiple Myeloma Research Project and the Belle S. and Irving E. Meller Center for the Biology of Aging. The Dr. Michael Baker Research Fellow Chair supports a Staff Scientist in Prof. Shachar’s lab.