One key component of the immune system that prevents breast cancer cells from forming distant metastases is a group of cells called natural killer cells. How breast tumor cells evade this surveillance system is not fully understood.
Now, scientists at Johns Hopkins University have discovered breast cancer cells can alter the function of natural killer (NK) cells in a way that promotes metastasis.
In a new study published in the Journal of Cell Biology, the team showed combining small-molecule inhibitors of DNA methyltransferases (DNMTs) with antibodies targeting the proteins TIGIT or KLRG1 could prevent this process and reduce the spread of breast cancer to distant organs.
Breast cancer cells are initially susceptible to being reined in by NK cells, the Johns Hopkins team found, suggesting the tumor cells must have developed strategies to overcome NK surveillance.
To test the theory, the researchers cultured tumor-exposed NK cells with tumor cell clusters in lab dishes. Surprisingly, they promoted the formation of new tumor colonies by almost twofold. Experiments in mice confirmed that tumor cells somehow educated NK cells to promote the spread of the cancer.
After their encounter with tumor cells, NK cells undergo dramatic changes in gene expression. The Hopkins scientists used RNA sequencing analysis to identify the molecular mechanisms behind that conversion.
Among the many proteins that seemed to be influencing NK cells, the team focused on two receptors, TIGIT and KLRG1. TIGIT has recently emerged as a hot immune checkpoint target for drug development. For example, Roche’s anti-TIGIT antibody tiragolumab, combined with PD-L1 blocker Tecentriq, recently showed improved tumor response over Tecentriq alone in metastatic lung cancer.
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Treatment with either anti-TIGIT or anti-KLRG1 antibodies prevented NK cells from helping breast cancer cells seed new tumor colonies, the Hopkins team reported. In addition, they found DNMTs were also highly expressed by tumor-exposed NK cells. Adding FDA-approved DNMT inhibitors decitabine and azacytidine to either one of the antibodies was even more effective at reducing metastases in lab dishes.
There has been much enthusiasm around developing anti-cancer therapies based on NK cells. In a new study in eLife, researchers at the National Institutes of Health described how engineering high affinity NK cells to express a PD-L1-targeting chimeric antigen receptor (CAR) slowed the growth of head and neck tumors in mice and also reduced the amount of immunosuppressive myeloid cells within the tumor. The researchers suggested that these CAR-expressing NK cells could be used in patients who are predicted to be insensitive to or have failed existing immunotherapy treatments.
Another team led by the University of California, San Diego recently created novel NK cells by removing a gene called CISH from them. That improved the functioning of the NK cells, which cleared leukemia in mouse models.
The Johns Hopkins team believes the combination of DNMT inhibitors with receptor-blocking antibodies could offer a new clinical strategy to revitalize NK cells so they can prevent breast cancer metastases.
“Combined with our observation that NK cells are abundant early responders to disseminated breast cancer cells, our data provide preclinical rationale for the concept of NK cell-directed immunotherapies in the adjuvant setting for breast cancer patients with high risk of metastatic recurrence,” said senior author Andrew Ewald, Ph.D., Hopkins professor and co-director of the Cancer Invasion and Metastasis Program in the Sidney Kimmel Comprehensive Cancer Center, in a statement.