Johns Hopkins University’s scientists have discovered that breast cancer cells can change the function in natural killer cells so they prevent metastases.
Natural killer (NK) cells play a significant role in the body’s defense against tumors and viral infections. The antitumor capacity involves an antimetastatic component, but it is now known that tumor cells can evade the antimetastatic effect of NK cells. Invasive breast cancer cells are vulnerable to healthy NK cells (unchanged NK cells not exposed to a tumor environment). The researchers found that NK cells exposed to cancer cells lose their cytotoxic and antimetastatic properties, allowing metastatic growth to proceed. The goal of a recent study was to determine how metastatic breast cancer cells escape NK-cell antimetastatic activity.
Primary tumor organoids (simplified 3-D cell-mass-derived organ models generated in vitro) were developed from cells isolated from laboratory mouse mammary tumors. Organoids and cell clusters from the organoids were co-cultured with healthy or tumor-exposed NK cells. Co-culture of the healthy NK cells led to a significant reduction in tumor organoid invasion within 24 hours of co-culture, and organoid growth was decreased.
The ability of healthy NK cells to impede tumor cells’ distant organ seeding was demonstrated by the NK cells’ ability to decrease colony formation by the co-cultured organoid-derived cell clusters. One of the mechanisms used by healthy NK cells to limit metastasis is apoptosis. This was measured via a caspase analysis approach. Caspase activity was observed in 43% of the organoid-only cultures, but in 85% of healthy NK-cell co-cultured organoids, suggesting a cytotoxic mechanism used by the NK cells.
Tumor-exposed NKs were not able to impede organoid invasion. Culturing tumor-exposed cells with tumor cell clusters was found to promote colony formation at a level twice that for healthy NK cell co-cultures. There are ligand-receptor interactions on NK cells that are associated with the production of cytokines. Obtained RNA-seq data showed an increased expression of inactivating receptors on tumor-exposed NK cells compared to healthy NK cells. This new understanding of NK cells in metastasis can form the basis of efforts to develop immunotherapies for breast and other cancers with a high-risk metastasis.
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Chan, I., Knútsdóttir, H., Ramakrishnan, G., Padmanaban, V., Warrier, M., & Ramirez, J. et al. (2020). Cancer cells educate natural killer cells to a metastasis-promoting cell state. Journal Of Cell Biology, 219(9). doi: 10.1083/jcb.202001134
Preventing breast cancer metastasis by reactivating natural killer immune cells. (2020). Retrieved 17 August 2020, from https://www.fiercebiotech.com/research/preventing-breast-cancer-metastasis-by-reactivating-natural-killer-immune-cells