Researchers find common mechanisms of the immune system

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ANN ARBOR, Michigan — To understand why some types of cancer manage to evade the immune system and grow unhindered, researchers have turned to pregnancy.

“During pregnancy, the immune system does not reject the growing fetus. Therefore, we know that there must be active mechanisms in the placenta. It is the same with cancer: the growing tumor is not rejected by the immune system. This means that the cancer cells have developed strategies to suppress immune rejection, just like in pregnancy,” said Dr. Weiping Zou.

In pregnancy, this is a good thing – it allows the baby to grow. But in cancer, it means that the tumor grows unchecked and treatments designed to trigger an immune response are not effective.

To understand this overlap, Zou collaborated with other researchers at the University of Michigan’s Rogel Cancer Center, bringing unique expertise in immunology, cancer genetics, gynecological pathology and medicinal chemistry.

They found that there is actually a molecular mechanism that is present in both cancer and pregnancy that suppresses the immune system. If you block this mechanism, called B7-H4, the immune system will go into overdrive to slow down cancer growth. Using mouse models and cell lines from breast and gynecological cancers, the researchers identified the hormone progesterone as a key regulator of the immune checkpoint B7-H4.

The article appeared in cell.

Expression of B7-H4 has previously been linked to shorter survival in cancer patients. The Rogel researchers discovered that B7-H4 plays an active role in regulating the immune system in both the placenta and the tumor microenvironment.

While the male hormone androgen had previously been associated with a suppression of the immune system in prostate cancer, it has now been shown for the first time that the female sex hormone progesterone influences the immune response in cancer.

Researchers used an inhibitor to block 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 significant but not dramatic.

“B7-H4 is an important checkpoint, but it is complicated,” Zou said. “Progesterone regulation is one mechanism, but we need more studies to understand whether other mechanisms are also involved in the regulation of B7-H4. We have no direct way to block this pathway. The receptors are still unknown. There is something in the basic immunobiology that we do not yet understand.”

The researchers plan further studies to investigate the mechanisms that regulate the stability of the B7-H4 protein, as well as the role that other factors play in cancer immunology.

Other authors: Jiali Yu, Yijian Yan, Shasha Li, Ying Xu, Abhijit Parolia, Syed Rizvi, Weichao Wang, Yiwen Zhai, Rongxin Xiao, Xiong Li, Peng Liao, Jiajia Zhou, Karolina Okla, Heng Lin, Xun Lin, Sara Grove, Shuang Wei, Linda Vatan, Jiantao Hu, Justyna Szumilo, Jan Kotarski, Zachary T. Freeman, Stephanie Skala, Max Wicha, Kathleen R. Cho, Arul M. Chinnaiyan, Samantha Schon, Fei Wen, Ilona Kryczek, Shaomeng Wang, Lieping Chen

Funding for this work is provided by National Cancer Institute grants CA217648, CA123088, CA099985, CA193136, CA152470, and CA46592; UTC-Yale Endowment

This work was supported by the following Rogel Cancer Center Shared Resources: Immunomonitoring, Transgenic Animal Models, Cell and Tissue Imaging

Disclosure: None

Cited paper: “Progestogen-controlled B7-H4 contributes to oncofetal immune tolerance,” cell. DOI: 10.1016/j.cell.2024.06.012

Resources:

Rogel Cancer Center of the University of Michigan, www.rogelcancercenter.org

Michigan Health Lab, www.MichiganHealthLab.org

Michigan Medicine Cancer AnswerLine, 800-865-1125

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