Cancer Cells Reprogram Immune Cells to Assist in Metastasis

Natural killer (NK) cells, a type of immune cell, are known to limit metastasis by inducing the death of cancer cells, but metastases still form in patients, so there must be ways for cancer cells to escape.

The loss of immunosurveillance is critical to breast cancer metastasis, immune checkpoint blockade has not been as effective in treating metastatic breast cancer as in melanoma or lung cancer. Breast cancer cells must overcome NK cell surveillance to form distant metastases, yet currently there is limited understanding of how metastatic cancer cells escape NK cell regulation.

Oncologists at the Johns Hopkins Kimmel Cancer Center (Baltimore, MD, USA) and their colleagues used ex vivo and in vivo models of metastasis, to establish that keratin-14+ breast cancer cells are vulnerable to NK cells. They then discovered that exposure to cancer cells causes NK cells to lose their cytotoxic ability and promote metastatic outgrowth.

Gene expression comparisons revealed that healthy NK cells have an active NK cell molecular phenotype, whereas tumor-exposed (teNK) cells resemble resting NK cells. Receptor–ligand analysis between teNK cells and tumor cells revealed multiple potential targets. The team next showed that treatment with antibodies targeting T cell immunoreceptor with Ig and ITIM domains (TIGIT), antibodies targeting killer cell leptin-like receptor G1 (KLRG1), or small-molecule inhibitors of DNA methyltransferases (DMNT) each reduced colony formation. Combinations of DNMT inhibitors with anti-TIGIT or anti-KLRG1 antibodies further reduced metastatic potential.

Isaac Chan, MD, PhD, a Medical Oncologist and lead author of the study, said, “Metastatic disease is the main driver of breast cancer deaths, and we need a deeper understanding of how and why it occurs. Our study has identified a new strategy for cancer cells to co-opt the immune system. If we could prevent or reverse natural killer cell reprogramming in patients, it could be a new way to stop metastasis and reduce breast cancer mortality.”

The authors proposed that NK-directed therapies targeting these pathways would be effective in the adjuvant setting to prevent metastatic recurrence. The process may also apply to other cancer types. Immunotherapies that target NK cells could also potentially be used together with existing immunotherapies that stimulate T cells to fight cancer. The study was published on July 9, 2020 in the Journal of Cell Biology.

Related Links:
Johns Hopkins Kimmel Cancer Center