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Analysis of endometrial mRNA in patients with different pregnancy outcomes after immunotherapy: A cohort study

ABSTRACT: Purpose: The efficacy of immunomodulators in improving pregnancy outcomes in infertile patients is controversial, with some reports finding improvements in pregnancy outcomes and some studies finding lack of efficacy in unselected patient populations. Therefore, the aim of this study was to identify people who could benefit from immunotherapy. Methods: 29 patients who had at least one previous embryo transfer failure and planned to undergo another frozen-thawed embryo transfer (FET) cycle were included. Peripheral blood of the patients was collected for detection of serum cytokines, T cell subsets at D3-D9 days of menstrual cycle before FET, mRNA was extracted from endometrial tissues during the window of implantation (WOI) for analysis. All patients began treatment with immunomodulators, including prednisone, hydroxychloroquine, cyclosporine, on the first day of the FET cycle. They were divided into pregnant group and non-pregnant group according to clinical pregnancy. Results: There were no differences in cytokines and T cell subsets between the two groups. Functional annotation of endometrial mRNA revealed functional enrichment in leucocyte mediated immunity, innate immune response, regulation of T cell receptor (TCR) signaling, T cell activation and positive T cell selection. Conclusion: The cytokines and immune cell subsets of peripheral blood cannot accurately predict the outcome of pregnancy after immunotherapy, and endometrial biopsy on the WOI may be a target to identify people who benefit from immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272778 | GEO | 2024/09/09

REPOSITORIES: GEO

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Project description:Background: a fundamental challenge for reproductive biology is to understand the menstrual cycle, specially the window of implantation, whose regulation and mechanistic remain incompletely understood in human reproductive physiology. Transcriptomics from a systems biology perspective provides a genomic framework to discover endometrial tissue specific regulation and behavior and its function in reproductive physiology. Results: Here, we applied a transcriptomic analysis of 238 endometrial receptivity related genes using a customized Agilent platform. 507 human endometrial biopsies were analyzed among the menstrual cycle, especially in the expected window of implantation and divided in to transcriptomic profiles using machine learning predictors (SVM and KNN models). The clinical relevance of these profiles was tested defining the best transcriptomic profile for pregnancy and live birth. Weighed Gene Co-expression Networks (WGCN) was applied is these clinically well-defined endometrial states to characterize the gene co-expression tissue specific regulation in humans for pregnancy in comparison with the other transcriptomic stages of menstrual cycle. For the first time, the menstrual cycle has been mapped as a percentage of positive and negative correlations between genes. Thanks to this approach, we have discovered the WOI as the fewest negatively correlated state with the highest proportion of positive correlations (Cochran´s Q = 14324.12, FDR < 2.2e-16) with an average of 84% of positive correlations in pregnant profile, while 53% in the two previous Proliferative (PF) and Early Pre-Receptive profiles and 67% in the late secretory endometrium, just before menstruation renewal. Finally, this study provides a wealth of network data to the scientific community to stimulate hypothesis-driven single-molecule endometrial studies in the form of a user-friendly database called the Menstrual Cycle Gene Co-expression Network (website: www.menstrualcyclegcn.com). Conclusions: this genomic research reveals for first time the pregnant endometrium as a global derepressed state in human menstrual cycle. This indicates the endometrium is generally a repressive tissue in human menstrual cycle with a relaxed WOI period where gene expression reaches the highest proportion of positive correlation, indicating that a decrease of inhibition may allow embryo implantation. Detailed molecular information about co-expression among menstrual cycle is also provided.

Project description:Interferon tau (IFNT), a Type I IFN similar to alpha IFNs (IFNA), is the pregnancy recognition signal, produced by the ruminant conceptus. To elucidate specific effects of bovine IFNT and of other conceptus-derived factors, endometrial gene expression changes during early pregnancy were compared to gene expression changes after intrauterine application of human IFNA2. In study one, endometrial tissue samples were obtained on days (D) 12, 15, and 18 post-mating from nonpregnant or pregnant heifers. In study two, heifers were treated from D14 to D16 of the estrous cycle with an intrauterine device releasing IFNA2 or placebo lipid extrudates or PBS only as controls. Endometrial biopsies were collected after flushing the uterus. All samples from both experiments were analyzed with an Affymetrix Bovine Genome Array. Study one revealed differential gene expression between pregnant and nonpregnant endometria on D15 and D18. In study two, IFNA2 treatment resulted in differential gene expression in the bovine endometrium. Comparison of the datasets from both studies identified genes that were differentially expressed in response to IFNA2 but not in response to pregnancy on D15 or D18. Vice versa, genes were found as differentially expressed during pregnancy but not after IFNA2 treatment. In study three, spatiotemporal alterations in expression of selected genes were determined in uteri from nonpregnant and early pregnant heifers using in situ hybridization. The findings of this study suggest differential effects of bovine IFNT compared to human IFNA2 and that some pregnancy-specific changes in the endometrium are elicited by conceptus-derived factors other than IFNT. Study I: Early pregnancy; day 12 of pregnancy (n=5 heifers), day 15 of pregnancy (n=3), day 18 of pregnancy (n=4), day 12 cyclic controls (n=5), day 15 cyclic controls (n=3), day 18 cyclic controls (n=4). Study II: Treatment with human interferon alpha (IFNA); IFNA treatment group (IFNA, n=3 heifers), placebo group (PLAC, n=3 heifers), control group (CONT, n=3 heifers).

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Analysis of endometrial mRNA in patients with different pregnancy outcomes after immunotherapy: A cohort study

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