Researchers have uncovered a similar molecular mechanism found in both cancer and pregnancy that suppresses the immune system. By targeting this mechanism, known as B7-H4, it is possible to boost the immune response to impede cancer growth. Through studies on mouse models and cell lines of breast and gynecologic cancers, the scientists have identified the hormone progesterone as a crucial regulator of the B7-H4 immune checkpoint.
In order to comprehend why certain cancers can evade the immune system and proliferate unchecked, researchers turned to the study of pregnancy.
“During pregnancy, the immune system does not reject the developing fetus, implying that there are active mechanisms at play in the placenta. In cancer, a similar phenomenon occurs where the growing tumor evades immune rejection. This indicates that cancer cells have devised tactics to suppress immune response, mirroring the mechanisms seen in pregnancy,” explained Dr. Weiping Zou.
While this mechanism is beneficial in pregnancy as it facilitates fetal growth, it becomes problematic in cancer by allowing unchecked tumor growth and rendering immune-boosting treatments ineffective.
To explore this connection, Zou collaborated with other researchers from the University of Michigan Rogel Cancer Center, combining expertise in immunology, cancer genetics, gynecologic pathology, and medicinal chemistry.
The study revealed a shared molecular mechanism in cancer and pregnancy that inhibits the immune system. By blocking this mechanism, B7-H4, the immune response can be boosted to inhibit cancer growth. The team pinpointed progesterone as a pivotal regulator of the B7-H4 immune checkpoint through their work with mouse models and cell lines of breast and gynecologic cancers.
This research has been published in Cell.
Prior studies have connected B7-H4 expression to decreased survival rates in cancer patients. The Rogel researchers have shown that B7-H4 actively moderates the immune system in both the placenta and the tumor microenvironment.
Additionally, while the male hormone androgen has previously been associated with immune suppression in prostate cancer, this study is the first to demonstrate the impact of the female hormone progesterone on immune response in cancer.
Scientists utilized an inhibitor to block progesterone signaling in mice with breast cancer and in human breast cancer tissue samples. This approach resulted in slowed cancer growth in mice and stimulated an immune response, although the effect was marked but not drastic.
“B7-H4 acts as a crucial checkpoint, yet its regulation is intricate,” stated Zou. “Progesterone regulation represents one aspect, but more research is needed to determine whether other mechanisms are involved in controlling B7-H4. At present, we lack a direct method to block this signaling pathway, with the receptors remaining unidentified. There are aspects in the fundamental understanding of immunobiology that we have yet to grasp.”
