Unveiling Progesterone's Impact on Cancer Immunosuppression

By studying how the immune response is suppressed during pregnancy, researchers have identified key mechanisms that prevent the immune system from blocking cancer.

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 is 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.”

Weiping Zou, M.D., Ph.D. University of Michigan

This mechanism is advantageous during pregnancy since it helps the unborn child thrive. However, in the case of cancer, it indicates that the tumor is growing unchecked and that immunostimulating therapies are ineffective.

To comprehend this overlap, Zou worked with fellow researchers at the University of Michigan Health Rogel Cancer Center, combining their distinct backgrounds in immunology, pharmaceutical chemistry, gynecologic pathology, and cancer genetics.

They discovered that, in fact, cancer and pregnancy share a biochemical pathway that inhibits the immune system. When this B7-H4 process is blocked, the immune system becomes more active and slows the spread of cancer. The hormone progesterone was found to be a crucial regulator of the B7-H4 immune checkpoint by the researchers after examining mice models and cell lines of breast and gynecologic malignancies.

In the past, B7-H4 expression has been linked to a lower chance of survival for cancer patients. The Rogel team found that B7-H4 actively regulates the immune system in the tumor microenvironment as well as the placenta.

Furthermore, progesterone, a female sex hormone, has never before been demonstrated to affect the immune response in cancer, despite the male hormone testosterone having been previously connected to immune suppression in prostate cancer.

Progesterone signaling was blocked by an inhibitor in human breast cancer tissue samples and mice with breast cancer, which slowed the cancer's growth and triggered the immune system. Still, the result was noticeable if not spectacular.

B7-H4 is an important checkpoint, but it is complicated, progesterone regulation is one mechanism, but we need more studies to understand whether other mechanisms are also involved in regulating B7-H4. We do not have a direct way to block this signaling pathway. The receptors remain unknown. There is something in the basic immunobiology that we still do not understand.”

Weiping Zou, M.D., Ph.D. University of Michigan

More research on the processes controlling the stability of the B7-H4 protein and the part other variables play in cancer immunology is planned.