Blocking PD-L1 Signaling Reduces Brain Metastasis Outgrowth

A recent study published in Cell shows that myeloid cells can suppress immune response—which allows breast cancer cells to metastasize to the brain to form secondary tumor cells there.

"We wanted to understand how the brain immune environment responds to the tumor, and there are so many different cells, and so many changes," said Siyuan Zhang from the Harper Cancer Research Institute and a co-author on the paper. "The traditional belief was that the process described in this paper would be anti-tumor, but in our case, after a lot of experimenting, we discovered it is a proponent of metastasis."

Through single-cell sequencing and an imaging technique, the researchers discovered that microglia promoted the outgrowth of breast cancer that has spread to the brain by the expression of several proteins. The microglia release one protein—an immune cell-attracting protein called CXCL10—to recruit more microglia to the metastasis. All these microglia express a protein named VISTA, which serves as protection against brain inflammation. But when faced with a cancer cell, this two-part process suppressed important T cells. 

The activation of the VISTA checkpoint had not previously been known as a potential promoter of brain metastasis, said the paper's lead author, Ian Guldner. In addition to using a mouse model for the research, the team used data mining techniques to validate how humans' brains would respond.

According to Guldner, the discovery is relevant because antibodies have been developed that blocked VISTA in humans. However, significant additional work needs to be performed to ensure the safe and effective use of VISTA-blocking antibodies in people with brain metastases. "The brain immune system is a very active field, since brain cells are dysregulated during the aging process," Zhang said.