Research Summary
Study Title: A Glucocorticoid-Fas axis controls immune evasion during metastatic seeding
Publication: Nature
Dana-Farber Cancer Institute authors: Judith Agudo, PhD
Judith Agudo, PhD
Summary: Cancer spreads, or metastasizes, when tumor cells shed from a primary solid tumor, for example in the breast, and embed in other organs, such as the lung, liver, and brain, and begin to grow. Most approaches to prevent this metastatic process aim to shrink or control the growth of the primary tumor. New research focused on triple negative breast cancer (TNBC) from the lab of Dana-Farber scientist Judith Agudo, PhD, has uncovered a potential way to stave off metastases by activating the immune system against tumor cells that have traveled to distant organs. Agudo and colleagues invented and used a novel tool called Jedi to locate tumor cells that have spread and evaded attack by the immune system in animal models. Using RNA sequencing and epigenetic tools, the team discovered that some tumor cells that seed new distal organs activate the glucocorticoid receptor that protects them from being killed by immune cells. The team also found that a medicine that is already U.S. Food and Drug Administration approved for other indications called mifepristone inhibits this receptor. The drug blocked the ability of tumor cells in the new organ to resist killing by immune cells and reduced the number of micro-metastatic locations observed in animal models. The addition of an anti-PD1 immune checkpoint inhibitor further reduced metastases and extended survival. This approach to harness the patients’ immune system against traveling tumor cells has so far only been tested in mice, but this study and previous research suggest that glucocorticoid receptor activity occurs in human samples of triple negative breast cancer and correlates with metastasis and worse outcomes.
Significance: Most patients with solid tumors, such as breast, prostate, and colon cancer, are at the highest risk of death when the cancer spreads to other organs. This study identifies a therapeutic approach to leverage the patients’ immune system to eliminate metastasizing tumor cells and prevent metastatic disease rather than having to treat it. If the strategy can be tested and verified in humans, it could open the door to more effective prevention of metastatic triple negative breast cancer, and possibly other solid tumors.
Funding: The National Science Foundation, the National Institutes of Health, the Parker Institute for Cancer Immunotherapy, the Cancer Research Institute, the New York Stem Cell