Preventing the Reprogramming of NK Cells Could Help Stop Breast Cancer Metastasis

Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body. Their study, published today in the Journal of Cell Biology (JCB), suggests that preventing this reprogramming might stop breast cancer from metastasizing to other tissues.

"Breast cancer cells must overcome NK cell surveillance in order to form distant metastases," says Andrew Ewald, senior author. "However, we do not fully understand how breast cancer cells escape NK cell-mediated immunosurveillance during their transit through the circulation and the initial seeding of distant organs."

Although metastasizing breast cancer cells are initially vulnerable to NK cells, they are quickly able to alter the behavior of their would-be killers, reprogramming them so that they actually promote the later stages of metastasis, Ewald and colleagues discovered. Using several new assays to model metastasis in the laboratory as well as experiments in mice, the researchers found that, after they encounter tumor cells, human and mouse NK cells lose the ability to restrict tumor invasion and instead help cancer cells form new tumors.

NK cells exposed to tumors undergo dramatic changes, turning thousands of genes on and off and expressing different receptor proteins on their surface. Ewald and colleagues found that antibodies targeting two key receptor proteins on the surface of NK cells, called TIGIT and KLRG1, prevented NK cells from helping breast cancer cells seed new tumors. The FDA-approved drugs decitabine and azacitidine had similar effects, likely because they prevent large-scale changes in gene activity by inhibiting enzymes known as DNA methyltransferases. 

The researchers found that combining decitabine or azacitidine treatment with anti-TIGIT or anti-KLRG1 antibodies was particularly effective at preventing NK cells from enhancing the metastatic potential of breast cancer cells.

"The synergistic effects of DNA methyltransferase inhibitors with receptor-blocking antibodies suggests a viable clinical strategy to reactivate tumor-exposed NK cells to target and eliminate breast cancer metastases," says Isaac Chan, lead author of the study.