By examining the immune system during pregnancy, researchers have uncovered the mechanism that may contribute to oncofetal immune tolerance, according to a recent study published by Yu et al in Cell.
Background
“In pregnancy, the immune system does not reject the growing fetus, so we know there must be mechanisms active in the placenta. In cancer, it’s the same thing: the growing tumor is not rejected by the immune system. It means the cancer cells have developed strategies to suppress immune rejection—same as in pregnancy,” emphasized senior study author Weiping Zou, MD, PhD, of the University of Michigan Health.
In pregnancy, immune system suppression allows the baby to grow; however, in cancer, this mechanism may promote unchecked tumor growth and reduce the efficacy of therapies designed to stimulate an immune response.
Study Methods and Results
In the recent study, a team of researchers with expertise in immunology, cancer genetics, gynecologic pathology, and medicinal chemistry explored potential mechanisms of immune system tolerance—with the goal of better understanding why some cancer types successfully circumvent the immune system.
The researchers were able to identify a molecular mechanism shared in cancer and pregnancy that suppresses the immune system. They discovered that B7-H4 played an active role in moderating the immune system in both the placenta and the tumor microenvironment. B7-H4 expression has previously been associated with poorer survival in patients with cancer.
By blocking the B7-H4 immune checkpoint, the immune system prepared to slow tumor growth. Using mouse models and cell lines of breast and gynecologic cancers, the researchers then found that the female sex hormone progesterone may be a key regulator of the B7-H4 immune checkpoint. They blocked progesterone signaling with an inhibitor in mice with breast cancer and in human breast cancer tissue samples—which slowed the cancer’s growth in mice and activated the immune response. Nonetheless, the effect was clear but not dramatic.
Conclusions
Although the male sex hormone androgen has previously been linked to immune suppression in prostate cancer, this was one of the first studies demonstrating that progesterone may influence immune response in cancer.
“B7-H4 is an important checkpoint, but it’s complicated. Progesterone regulation is one mechanism, but we need more studies to understand whether other mechanisms are also involved in regulating B7-H4,” underscored Dr. Zou. “We do not have a direct way to block this signaling pathway. The receptors remain unknown. There’s something in the basic immunobiology that we still don’t understand,” he concluded.
The researchers plan to conduct additional studies analyzing the mechanisms regulating B7-H4 protein stability as well as the role other factors may play in cancer immunology.
Disclosure: The research in this study was funded by the National Cancer Institute and the UTC-Yale Endowment. For full disclosures of the study authors, visit cell.com.
