Breakthrough Breast Cancer Treatment Shows Promise for Multiple Cancers, Weizmann Scientists Report

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“Build your enemy a golden bridge to retreat across,” a piece of advice from Sun Tzu’s The Art of War, reflects a strategy employed by cancerous growths against the immune system. A new study in Cell Reports by researchers from Prof. Idit Shachar’s lab at the Weizmann Institute of Science reveals that an aggressive form of breast cancer induces nearby immune cells to form “molecular bridges” between themselves, suppressing immune attack and fostering immune tolerance. In a mouse model, an antibody treatment that blocks the formation of these bridges restored the immune system’s ability to attack, inhibiting cancer progression.

Historically, cancer treatment focused on directly destroying malignant cells through methods like radiation and chemotherapy. However, it’s now understood that tumor development relies on communication between cancer cells and surrounding noncancerous cells. Previous research from Shachar’s lab in Weizmann’s Systems Immunology Department demonstrated that blood cancer cells create “molecular bridges” with nearby support cells for survival and proliferation; without these bridges, they die within days.

The researchers identified the CD84 (SLAMF5) protein as the building block for these bridges: when present on the surface of an immune cell, it binds to a similar protein on another cell, forming an intercellular connection. In the studied blood cancer, CD84 is highly expressed on the cancer cells themselves, creating physical bridges between them and adjacent cells. The researchers even developed an antibody that blocks these bridges, slowing disease progression, which led to a collaboration with the City of Hope cancer treatment and research center in California.

“We are presenting a treatment that might help a wide range of patients, since it focuses on the tumor microenvironment and not on the cancer cells themselves”

“We then wanted to see whether the molecular bridges between cells in the tumor’s microenvironment are also important in types of cancer other than blood malignancy,” Shachar says. “Dr. Steven Rosen, an executive vice president at City of Hope, proposed that we examine samples from patients with the most aggressive type of breast tumors – triple-negative breast cancer. One of the reasons there is still no cure for these tumors is that their cells show no external signs that would allow us to identify and destroy them. That’s why it is especially important to find a treatment that can suppress the cancer by affecting a component of its supportive microenvironment, rather than the cancer cells themselves.”

In the new study, led by Stav Rabani, a doctoral student in Shachar’s lab, the researchers analyzed the genetic sequences of growths taken from women with triple-negative breast cancer and discovered that the level of CD84 expression in the tumor microenvironment was much higher than normal. One of the surprising findings of the study was that even though breast cancer cells themselves express very low levels of CD84, they cause 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 did not survive as long as others.

The City of Hope cancer treatment and research center, together with Yeda Research and Development Co Ltd, the commercial arm of the Weizmann Institute of Science, set up a company called Slam BioTherapeutics, which is developing cancer treatments based on anti-SLAM family antibodies. “The antibody we developed only works on cells that express a high level of CD84,” Shachar explains. “In a healthy person, most of the cells do not express this protein at all and immune cells express it at low levels, so the treatment works specifically in the tumor microenvironment. The company is currently focusing on using anti-SLAM antibodies to treat blood cancers in which the cancer cells themselves express high levels of CD84, but our new findings open the door to trying the antibody on many other kinds of growth, including those in which the cancerous cells don’t express this protein at a high level. In the age of personalized medicine, we are presenting a treatment that could help a wide range of patients since it focuses on the tumor microenvironment and not on the cancer cells themselves.”