Completed Cancer Infection & Immunity

Unravelling the CTLA-4 immune checkpoint: from cell biology to clinical application.

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £1.7M
Period Feb 2018 — Feb 2023

In plain English

AI plain-English summary

The CTLA-4 pathway acts as a molecular brake on the immune system, and when it fails, the body can attack itself. Despite its central role in preventing autoimmune diseases and its use in cancer therapies, scientists still do not understand the basic mechanics of how CTLA-4 interacts with its two partner molecules, CD80 and CD86. This project aims to fill that gap by answering three concrete questions: how CTLA-4 physically captures and transfers these ligands between cells, how those interactions change its function, and what newly discovered patient mutations reveal about the pathway. This is fundamental science—there is no immediate clinical product or diagnostic test on the horizon. But the knowledge could eventually help researchers design better immune-modulating drugs, predict which patients will respond to existing checkpoint therapies, or interpret the growing number of CTLA-4 mutations found in patients with severe autoimmune disorders. Past work on this same pathway has already transformed cancer treatment; a deeper molecular understanding could unlock the next step.

View original technical description
The CTLA-4 pathway is a key immune regulator whose absence or mutation leads to profound autoimmunity. CTLA-4 and its relative CD28 have opposing inhibitory and stimulatory functions respectively and interact with two ligands CD80 and CD86. Despite the key role of this pathway in immune regulation and high profile therapies in tumour immunology, our understanding of how CTLA-4 functionally interacts with its two natural ligands is remarkably incomplete. The aim of this proposal is to generate a robust molecular, cellular and functional framework for CTLA-4 biology which can be used to understand the impact of disease mutations, which are being identified as a result of next generation sequencing programmes, and generate knowledge which can underpin new approaches to manipulation of this key immune axis. We will address three key aims: 1). What is the cellular machinery used by CTLA-4 to capture and transfer ligands between cells? 2). How do CTLA-4 interactions with its natural ligands influence its function? 3). How do clinically identified mutations inform our understanding of the CTLA-4 pathway?

View the original record at the funder ↗

Researchers

David Sansom (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Applying advanced understanding of CTLA-4 function to optimise therapies for autoimmunity
Towards an integrated understanding of the CD28/CTLA4 immune checkpoint in the regulation of autoimmunity
Characterising the molecular interactions in the CTLA-4 and PD-1 pathways as a basis for novel strategies in immune checkpoint blockade
Understanding the relationship between clathrin-mediated endocytosis and transendocytosis of CTLA-4: cell biology at the heart of immune regulation.
What is the molcular basis of CTLA-4 trans-endocytosis?

Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.