A conditional mouse model for human MUC1-positive endometriosis shows the presence of anti-MUC1 antibodies and Foxp3+ regulatory T cells

Abstract

SUMMARYEndometriosis is defined by the presence of tissue implants resembling endometrial glands outside of the uterus, at ectopic sites, frequently on the ovarian surface. The ectopic lesions are often invasive, resistant to therapy, and may predispose to endometrioid and clear cell ovarian tumors. The complex mechanisms leading to chronic endometriosis are mediated partly by impaired immune surveillance in the host. Although innate immunity has been addressed previously, the response of adaptive immune effectors to specific antigens has not been characterized, mostly because very few endometriosis antigens have been defined to date. We postulated that the mucin 1 (MUC1) glycoprotein, which is normally present on eutopic human endometrial glands and overexpressed in endometrioid and clear cell ovarian tumors, is also present in ectopic lesions of ovarian endometriosis. Furthermore, changes in MUC1 expression in endometriosis could promote adaptive anti-MUC1 immunity that might play a role in the malignant progression. To test our hypothesis, we crossed MUC1 transgenic mice, which express human MUC1 under the endogenous promoter, with the loxP-Stop-loxP-Kras G12D/+ (Kras) mice, in which endometriosis can be induced through Cre-loxP recombination. The double transgenic MUC1Kras mice develop benign, MUC1-positive ovarian lesions, closely resembling human endometriosis. Subsequent to disease induction, the mice generate high titers of IgM and IgG antibodies that are specific for MUC1. Antibodies appear early in disease and the predominance of the IgG1 subclass suggests Th2-driven immunity. Immune phenotyping revealed an accumulation of Foxp3+ CD4 regulatory T cells (Tregs) in the draining lymph nodes at late-stage disease. Furthermore, our observations in human endometriosis showed a similar recruitment of FOXP3+ CD4 T cells. Overall, our results reveal a Th2/Treg-dominant natural immunity in endometriosis with potential implications for cancer progression.

Immunobiology of human mucin 1 in a preclinical ovarian tumor model

“…No histological modifications of the ipsilateral oviduct and uterine horn were observed, confirming that intrabursal AdCre injections remain anatomically confined, as previously demonstrated by us and others using reporter gene experiments. 9,34 …”

“…The only two existing preclinical cancer models for de novo tumors expressing MUC1 as self are for colon and pancreatic adenocarcinomas. 22,45,46 We describe here the first preclinical ovarian tumor model, which expresses human MUC1 antigen as a self molecule, using triple Tg MUC1KrasPten mice that carry the previously reported, loxP-engineered Kras and Pten loci, 9,34 while co-expressing MUC1 antigen, driven by the endogenous mucin 1 promoter. 33 The tumors develop at the primary site, metastasize throughout the peritoneal cavity and on the diaphragm and are accompanied by increased circulating MUC1 levels, replicating more closely the human disease.…”

Interplay between Misplaced Müllerian-Derived Stem Cells and Peritoneal Immune Dysregulation in the Pathogenesis of Endometriosis

“…Tregs are characterized by FOXP3 and produce IL-10 and TGF- β , suppressing activation of the immune system and thereby maintaining immune system homeostasis and tolerance to self-antigens [78–82]. A mouse model study [83] reported in late-stage of the disease a switch toward Th2 and Treg cell profiles, with an overrecruitment of Foxp3 + CD4 + Tregs in the draining lymph nodes. This is congruent with our previous reported results [34].…”

Chronic inflammation in endometriosis and endometriosis-associated ovarian cancer: New roles for the “old” complement pathway

“…To further explore this mechanism, we employed triple transgenic mice that progress to EAOC closely mirroring the human disease. 6,7 Using this preclinical model, we demonstrated that complement upregulation in epithelial cells occurs early in carcinogenesis.…”