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Towards reproducible research in recurrent pregnancy loss immunology: Learning from cancer microenvironment deconvolution.

ABSTRACT: The most recent international guidelines regarding recurrent pregnancy loss (RPL) exclude most of the immunological tests recommended for RPL since they do not reach an evidence-based level. Comparisons for metanalysis and systematic reviews are limited by the ambiguity in terms of RPL definition, etiological and risk factors, diagnostic work-up, and treatments applied. Therefore, cohort heterogeneity, the inadequacy of numerosity, and the quality of data confirm a not standardized research quality in the RPL field, especially for immunological background, for which potential research application remains confined in a separate single biological layer. Innovative sequencing technologies and databases have proved to play a significant role in the exploration and validation of cancer research in the context of dataset quality and bioinformatics tools. In this article, we will investigate how bioinformatics tools born for large-scale cancer immunological research could revolutionize RPL immunological research but are limited by the nature of current RPL datasets.

SUBMITTER: Betti M

PROVIDER: S-EPMC9996132 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Towards reproducible research in recurrent pregnancy loss immunology: Learning from cancer microenvironment deconvolution.

Betti Martina M Vizza Enrico E Piccione Emilio E Pietropolli Adalgisa A Chiofalo Benito B Pallocca Matteo M Bruno Valentina V

Frontiers in immunology 20230223

The most recent international guidelines regarding recurrent pregnancy loss (RPL) exclude most of the immunological tests recommended for RPL since they do not reach an evidence-based level. Comparisons for metanalysis and systematic reviews are limited by the ambiguity in terms of RPL definition, etiological and risk factors, diagnostic work-up, and treatments applied. Therefore, cohort heterogeneity, the inadequacy of numerosity, and the quality of data confirm a not standardized research qual ...[more]

PMID: 36911667

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Project description:Study questionWhat is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature?Summary answerThe guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized.What is known alreadyA previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update.Study design size durationThe guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes.Participants/materials setting methodsBased on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee.Main results and the role of chanceThe guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations - of which 31 were formulated as strong recommendations and 29 as conditional - and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL.Limitations reasons for cautionSeveral investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised.Wider implications of the findingsThe guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL.Study funding/competing interestsThe guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker's fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker's fees from Ferring. The other authors report no conflicts of interest.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

Project description:We have identified a mechanism by which cytomegalovirus (CMV) interleukin-10 (IL-10) is utilized by glioblastoma multiforme (GBM) to maintain the immunosuppressive microenvironment. CMV has been ubiquitously detected within high-grade gliomas, but its role has not been fully elicited. GBMs harvested ex vivo were analyzed by flow cytometry to determine CMV antigen expression. Distinct expressing subsets of cells, such as the myeloid lineage and CD133+ cells, were identified. CMV antigens US28, pp65, IE1, and gB were also present within four individual and fully characterized human GBM-derived glioma cancer stem cell (gCSC) populations as ascertained by flow cytometry. These gCSCs produce CMV IL-10 in a range from 5.62 to 111.11 pg/mL/106cells/day. When human CD14+ monocytes, precursor cells to macrophages/microglia, were exposed to gCSC-conditioned medium or recombinant CMV IL-10, there was a marked increase in the expression of immune-suppressive factors such as B7-H1, p-STAT3, VEGF, and TGF-beta. Concurrently, anti-tumor and pro-immune MHC II and CD86 were down-regulated and the expression pattern of immune markers was similar to the phenotype of glioma-associated macrophages/microglia. Exposure of CD14+ cells to CMV IL-10 induced the up-regulation of IE1, a marker of transcriptional activity of CMV. Chemotaxis assays revealed that the supernatant from CD14+ cells exposed to CMV IL-10 was able to induce the migration of gCSCs compared with the supernatant from CD14+ cells cultured in medium alone. This result indicates that CMV subverts GBM-associated macrophages/microglia to support the immune-suppressive microenvironment by shifting their phenotype to the immune-suppressive M2. The shift is subsequent to activation of the STAT3 pathway, resulting in the propagation of glioma angiogenesis via an increase in VEGF and by increasing glioma invasion. Therapeutic strategies involving immune-mediated cytotoxic responses now include strategies to reverse tumor-mediated immune suppression. This study suggests that including CMV as a target could enhance the effectiveness of immunotherapy.

Dataset Information

Towards reproducible research in recurrent pregnancy loss immunology: Learning from cancer microenvironment deconvolution.

Publications

Towards reproducible research in recurrent pregnancy loss immunology: Learning from cancer microenvironment deconvolution.

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