Pregnancy requires adjustments in the mother’s immune system to avoid rejection of the semi-foreign fetus and to avoid complications of pregnancy later on, and these complex adjustments are associated with interactions between immune factors.
While these immune modifications are beneficial because they allow the embryo to grow, activating similar mechanisms in cancer means that the tumor may grow unchecked, and treatments aimed at stimulating an immune response may not be effective.
“In pregnancy, the immune system does not reject the growing fetus, so we know that there are active mechanisms in the placenta,” Weiping Zhu, a Ph.D., told EurekAlert. “The same thing happens in cancer: the growing tumor is not rejected by the immune system. This means that cancer cells have developed strategies to suppress immune rejection, just as happens in pregnancy.”
Researchers turned to pregnancy to understand why some cancers are able to bypass the immune system and grow unchecked. Zou collaborated with other researchers from the Rogel Cancer Center at the University of Michigan in the United States, bringing together unique expertise in immunology, cancer genetics, gynecology and medicinal chemistry.
Mechanism of immunosuppression
Researchers have found that a molecular mechanism called P7H4 is involved in suppressing the immune system in pregnancy and cancer, and when this mechanism is disrupted, the immune system is activated to slow the growth of cancer.
Looking at mouse models and breast and gynecological cancer cells in the lab, the researchers identified progesterone as a key regulator of the P7H4 immune checkpoint.
While the male hormone androgen has previously been linked to immune suppression in prostate cancer, this is the first time the female hormone progesterone has been shown to influence the immune response in cancer.
What we don’t know about immunity
In the study, published in the journal Cell on July 4, researchers used an inhibitor to disrupt progesterone signaling in mice with breast cancer and in human breast cancer tissue samples, which slowed cancer growth in mice and activated the immune response. The effect was clear but not significant.
“P7H4 is an important but complex checkpoint,” Zou said. “Progesterone regulation is one mechanism, but we need more studies to understand whether other mechanisms are also involved in P7H4 regulation. We don’t have a direct way to disrupt this signaling pathway, the receptors are still unknown, and there is something in the basic immunobiology that we still don’t understand.”
The researchers plan to conduct additional studies to look at the mechanisms that regulate the stability of the P7H4 protein, as well as the role of other factors in cancer immunology.