First example of using single-cell RNA sequencing to find a therapeutic target

A new therapeutic target for inflammatory diseases such as asthma and autoimmune disorders has been identified by scientists at the Wellcome Trust Sanger Institute.  Published in Nature today, the researchers found that the PD-1 protein is a marker for developing Innate Lymphoid Cells that can trigger asthma.

PD-1 is an existing drug target for some cancers.  These findings show that drugs that target PD-1 could also be developed for treating asthma and other inflammatory diseases.

In the first example of using single-cell RNA sequencing to find a therapeutic target, the study also follows how Innate Lymphoid Cells develop. Understanding the biology behind this could help improve PD-1 cancer drugs, which are currently only effective for 20 per cent of patients.

Immune diseases occur when the immune system either fails to remove unwanted cells, such as during infection or cancer, or becomes too active and attacks healthy cells in the body, causing autoimmune diseases or allergies such as asthma.

Innate lymphoid cells (ILC cells) are a recently discovered group of cells in the immune system.  Of these, ILC2 cells are important in immune responses against infections and in asthma.  The levels of ILC2 cells rise enormously when activated by pollen or toxins, causing lung inflammation, but little is known about how they develop from ILC progenitor cells in the bone marrow or whether there are new specific markers for the activated ones.

Using Single-Cell RNA sequencing, the researchers studied hundreds of bone marrow cells from mice to investigate how ILCs develop. They were able to clearly identify progenitor cells and different levels of ILC development, and found that the progenitor cells displayed PD-1 protein on their surfaces.  Crucially, activated ILC2 cells also displayed high levels of PD-1, which permitted removal of these potentially dangerous cells by a simple antibody treatment targeting PD-1.

“Finding that PD-1 is a marker for the ILC progenitor cells and for activated ILC2s is a really exciting discovery – no-one has seriously looked at this before. It is a very happy coincidence that this interesting gene is already being explored as an immune therapy target for cancer treatment. Antibody drugs targeting PD-1 and thus affecting PD-1-expressing cells may be able to prevent the over-active immune response of ILC2 cells, and reduce or remove asthma symptoms.”

Dr Pentao Liu, from the Sanger Institute

Single-cell RNA sequencing analysis of innate lymphoid progenitors

rna-seq

a, Biaxial t-SNE clustering plot of 325 WT Lin-Flt3lo/-IL-7Rα+/loα 4β 7+ BM cells. Each point represents an individual cell. Cells were grouped into 10 distinct clusters (C1-10, colored differently). b, Distribution of gene expression in t-SNE plot. The color key indicates the expression level. c, Violin plots comparing expression of key ILC regulators in different clusters. The y-axis indicates the log2 (normalized count+ 1) expression levels. The black point indicates the mean of expression level. d, Heatmap of the expression levels of selected genes in different clusters.

 

PD-1 expression on immune T cells has been previously implicated in the failure of T cells to kill cancer, and therapies with antibodies that target PD-1 on T cells have already been developed for cancers such as melanoma. With the discovery of PD-1 on the ILC cells, scientists hope that these existing drugs and new ones may be able to improve cancer therapy or help asthma sufferers.

“This study helps us understand the biology of the immune system in ways that were impossible previously. If we want to know how to affect the activity of the ILC cells, we need to know how they develop and what switches them on and off. Not only is this useful for asthma and other inflammatory diseases, it could also help us understand what is happening during PD-1 cancer treatment and could potentially make that cancer therapy more effective.”

Dr Yong Yu, the first author from the Sanger Institute

“This is a great step forward in our understanding of immune cells. Finding that PD-1 is expressed on activated ILC2 cells gives us an opportunity to manipulate these cells. Further research in this area is needed to help improve immune function as well as prevent immune-mediated inflammatory disease.”

Dr Andrew McKenzie, an author on the paper from the MRC Laboratory of Molecular Biology

Source – Wellcome Trust Sanger Institute

Yu Y et al. (2016) Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its developmental pathway. Nature [Epub ahead of print]. [abstract]

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