Biology subjects

Efremova, M.

Publications and source records attributed to Efremova, M..

3 recordsLinked to original sources

bioRxiv2018

Reconstructing the human first trimester fetal-maternal interface using single cell transcriptomics

During the early weeks of human pregnancy, the fetal placenta implants into the uterine mucosa (decidua) where placental trophoblast cells intermingle and communicate with maternal cells. Here, we profile transcriptomes of [~]50,000 single cells from this unique microenvironment, sampling matched first trimester maternal blood and decidua, and fetal cells from the placenta itself. We define the cellular composition of human decidua, revealing five distinct subsets of decidual fibroblasts with differing growth factors and hormone production profiles, and show that fibroblast states define two distinct decidual layers. Among decidual NK cells, we resolve three subsets, each with a different immunomodulatory and chemokine profile. We develop a repository of ligand-receptor pairs (www.CellPhoneDB.org) and a statistical tool to predict the probability of cell-cell interactions via these pairs, highlighting specific interactions between decidual NK cells and invading fetal extravillous trophoblast cells, maternal immune and stromal cells. Our single cell atlas of the maternal-fetal interface reveals the cellular organization and interactions critical for placentation and reproductive success.

developmental biology↗

bioRxiv2018

A novel innate lymphoid cell delineates childhood autoimmune arthritis

Inflammation in autoimmune disease is mediated by a complex network of interacting cells. Their identity and cross-talk are encoded in messenger RNA (mRNA). Juvenile idiopathic arthritis (JIA), a chronic autoimmune arthritis of childhood, is characterised by synovial inflammation with infiltration of both innate and adaptive immune cells1. Activated T cells play a role in disease2 but the cell types that drive the recruitment and activation of immune cells within the synovium are not known. Here, we utilised droplet-based and full length single cell mRNA sequencing to obtain a quantitative map of the cellular landscape of JIA. We studied 45,715 cells from the synovial fluid of inflamed knee joints and peripheral blood. We identified a population of synovial innate lymphoid cells (ILCs), shared across patients, that exhibited a unique transcriptional profile in comparison to canonical ILC subtypes. Validation at protein-level across a spectrum of autoimmune arthritides revealed that these ILCs are pathologically expanded in a particular type of JIA. Using statistical tools to assess cellular interactions in synovial fluid, ILCs emerged as a central node of communication, expressing the full repertoire of genes required to orchestrate and maintain the inflammatory milieu. Several ILC-mediated signalling pathways may lend themselves as novel therapeutic targets. Together our findings demonstrate a distinct ILC subtype associated with a tissue-specific childhood autoimmune disease.

immunology↗

bioRxiv2017

Targeting the PD-1/PD-L1 pathway potentiates immunoediting to counterbalance neutral evolution in a mouse model of colorectal cancer

The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing the genome. However, to what extent immunoediting is shaping the cancer genome is still a matter of debate. Moreover, the impact of cancer immunotherapy with checkpoint blockers on modulating immunoediting remains largely unexplored. Here we elucidated the impact of evolutionary and immune-related forces on editing the tumor in a mouse model of colorectal cancer (CRC). We first show that MC38 cell line is a valid model for hypermutated and microsatellite-unstable (MSI) CRC. Analyses of longitudinal samples of wild type and immunodeficient RAG1 knockout mice transplanted with MC38 cells revealed that upregulation of checkpoint molecules and infiltration of Tregs are the major tumor escape mechanisms. Strikingly, the impact of neutral evolution on sculpting the tumor outweighed immunoediting. Targeting the PD-1/PD-L1 pathway potentiated immunoediting and rendered tumors more homogeneous in the MC38 model. The immunoediting effects were less pronounced in a nonhypermutated/MSI- model CT26. Our study demonstrates that neutral evolution is the major force that sculpts the tumor, and that checkpoint blockade effectively enforces T cell dependent immunoselective pressure in a hypermutated/MSI model of CRC.

genomics↗