This advance offers new perspectives for strengthening the therapeutic arsenal against the most insidious cancers.
- By analyzing single-cell RNA sequencing data from multiple human cancer types and the maternal-fetal interface, the researchers discovered that the B7-H4 protein is an onco-fetal immune tolerance checkpoint.
- They also showed that this protein was activated via the PR-P300-BRD4 axis under the influence of progesterone, allowing it to exert a crucial effect in tumor progression by escaping the immune system.
- “B7-H4 is an important control point, but it is complicated,” explained study co-author Prof. Zou, who is already planning further research with his colleagues to explore the mechanisms regulating B7-H4 stability.
The immune system destroys any foreign body in the body… except during pregnancy, a period during which the woman’s body tolerates the being that is developing inside her uterus. This is possible in particular thanks to the production by the fetus of molecules that inhibit the maternal immune system.During pregnancy, the immune system does not reject the growing fetus, so we know that there are mechanisms active in the placenta. In the case of cancer, it is the same: the growing tumor is not rejected by the immune system. This means that cancer cells have developed strategies to suppress immune rejection, as during pregnancy”, said Prof. Weiping Zouco-author of a new study conducted in collaboration with researchers at the University of Michigan Rogel Cancer Center, and published in review Cell.
Immune tolerance mechanisms common to cancer and pregnancy
Through cross-analysis of single-cell RNA sequencing data from multiple human cancer types and the maternal-fetal interface, researchers discovered that B7-H4 is an onco-fetal immune tolerance checkpoint. Under the influence of progesterone, this protein is activated via the PR-P300-BRD4 axis, allowing it to exert a crucial effect in tumor progression by evading the immune system.
Towards a treatment of tumors expressing B7-H4?
By identifying that B7-H4 expression is regulated by a specific enhancer, the researchers are opening the way to new therapeutic strategies. Experiments have shown that progesterone receptor antagonists or BRD4 inhibitors can make tumors expressing B7-H4 more sensitive to immunotherapy, thus offering a promising avenue for specifically targeting these types of cancers.
“The B7-H4 is an important checkpoint, but it is complicated, explained Professor Zou. Progesterone regulation is one mechanism, but we need more studies to understand if other mechanisms are also involved in B7-H4 regulation. We don’t have a direct way to block this signaling pathway. The receptors remain unknown. There is something in the basic immunobiology that we still don’t understand.”
The researchers plan additional studies examining the mechanisms regulating B7-H4 protein stability, as well as the role played by other factors in tumor immunology.