In about 10% of women, endometrium-like tissues (known as lesions) also grow outside of the uterus, leading to endometriosis. Endometriosis is characterised by pain and can cause infertility, but its molecular mechanisms and drivers remain unknown. Now, a comprehensive study reveals how lesions escape immune surveillance, by taking advantage of mechanisms for the body tolerating a foetus during pregnancy.
Definitive diagnosis and clinical response still present significant challenges, with a common treatment being hormonal therapy with surgery. Unfortunately, surgery must be repeated if lesions recur, and they often do. To improve the situation, a better understanding of how and why the lesions grow, their cellular makeup, their microenvironments, and other aspects of their biology is essential.
The Jackson Laboratory’s (JAX) Elise Courtois, PhD, in partnership with UConn Health’s gynaecological surgeon Danielle Luciano, MD, recently completed an important study to develop a comprehensive cell atlas of the disease based on lesions obtained from 14 individuals who had treatment for endometriosis
The paper, published Nature Cell Biology, includes a thorough comparison of healthy endometrium tissue and ectopic (outside their normal site) lesions. The data also describes the endometriosis microenvironment and the conditions that allow the lesions to form and grow in what should be unhospitable regions.
“The study builds a robust foundation for a better understanding of endometriosis and how it grows,” said Dr Luciano. “It’s exciting progress that we hope leads to earlier diagnosis and the ability to specifically target these abnormal cells for better treatments.”
The research team worked with tissues from individuals who had lesion removal at UConn Health for relief of symptoms. All were also receiving hormone therapy, the most frequent endometriosis management strategy. Not surprisingly, given that lesions are described as endometrial-like tissues growing in the wrong place, the cellular composition of the lesions in the peritoneum were quite similar to that of the normal endometrium. On the other hand, ovarian lesions had extensive differences in both composition and gene expression from the peritoneal ones. So while both ovary and peritoneum are receptive to the formation of lesions, they represent different environments and lead to important cellular and molecular differences between the two sites. The finding indicates that site-specific therapeutic design may be necessary to develop more effective treatments.
Another aspect of endometriosis is that, like cancer, the lesions represent abnormal growth that would typically be eliminated by immune surveillance. The researchers therefore investigated the immune cells in the peritoneal lesion microenvironment to see why they do not eliminate the abnormal lesion cells. They found that macrophages and dendritic cells contribute to conditions that promote immune inhibition and the promotion of immunosurveillance escape. Their specific characteristics are similar to those associated with foetal tolerance during pregnancy, which suggests that endometriosis hijacks a necessary, naturally occurring immune process to allow for lesion formation and persistence.
The paper details other aspects of both normal endometrium and ectopic lesions, including properties of vascularisation and the drivers of regeneration in endometrium and, perhaps, the formation of lesions in endometriosis. Of particular interest were key differences in the vascularisation of peritoneal versus ovarian lesions, further emphasising the site-specific nature of endometriosis. Also of note was the identification of a previously uncharacterised population of epithelial cells that may be progenitor cells for both endometrium and lesion formation, but more work is needed to define their precise role.
“Single cell analyses and hyperplexed antibody-based imaging techniques offer powerful insights into the complexity of the endometriosis microenvironment,” said Dr Courtois. “Understanding this complexity will be key for developing the new, efficient diagnostic and therapeutic tools that are so badly needed.”
Overall, the data captures a full description of endometrium and lesions, laying a strong foundation for understanding the vital cellular players and molecular dynamics of the disease. The data represents an important step forward for research into endometriosis and provides essential information for future therapeutics and diagnostics that can provide relief for those with this under-investigated disease.
Source: University of Connecticut
