Completed Infection & Immunity Cancer

Designing unconventional peptide modifications to universally enhance CD4+ T-cell activation

Funder Wellcome Charity-funded
Recipient organisation Cardiff University
Funding £1.8M
Period May 2018 — May 2023

In plain English

AI plain-English summary

Vaccines often fail because the immune system’s CD4+ T-cells do not grab hold of the peptide fragments presented on infected or cancerous cells tightly enough. This project aims to chemically modify those peptide fragments—specifically in the regions that flank the core binding site—so that T-cell receptors latch on with higher affinity, without losing the ability to distinguish friend from foe. The problem is that most vaccine studies ignore the strength of this molecular handshake. Weak binding between T-cell receptors and peptide-loaded HLA class II molecules is a major reason cancer vaccines underperform and why some people cannot clear persistent infections like HIV. This research directly targets that weakness. If it succeeds, the approach could allow researchers to design bespoke vaccines tailored to an individual’s HLA type—their personal immune fingerprint. That would transform vaccine design from a one-size-fits-all model into a personalised treatment, potentially improving responses to both infectious diseases and cancer. The work is tested in HLA-transgenic mice, so it remains at the fundamental science stage, but the underlying principle—that boosting receptor-ligand affinity can enhance T-cell activation—is already supported by evidence from long-term HIV controllers.

View original technical description
The CD4+ T-cell response is of fundamental importance in generating effective immunity to pathogens and cancer. The interaction of the CD4+ T-cell receptor (TCR) with peptide presented by HLA class II heterodimers (pHLA-II) is the central point of the adaptive immune response. Overwhelming evidence suggests the affinity of this interaction dictates the efficacy of T-cell activation (Panhuys et al Immunity 2014), and indeed, the fundamental importance of TCR:pHLA-II affinity was illustrated in a cohort of long term HIV controllers (Benati et al JCI 2016). Crucially, low affinity TCR:pMHC interactions contribute significantly to cancer vaccine failures. The biology of this interaction has been ignored by the vast majority of vaccine studies. This project takes a fundamentally different approach to therapeutic and prophylactic vaccines, by focusing on the details of the TCR:pMHC-II interaction. We aim to utilise our proven ability to generate high affinity TCR:pMHC-II interactions, with no loss of specificity, by targeting changes in the epitope flanking regions. This approach will illustrate how HLA-bespoke vaccines can be generated, and will be tested (using HLA-DR-transgenic mouse) in models of infection and cancer. The long term aim is to match superior vaccines to the individuals' HLA background, personalising treatment, and transforming vaccine design.

View the original record at the funder ↗

Researchers

Andrew Godkin (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Understanding HLA-E biology to advance therapeutic targeting in cancer
Improving T cell Functional Avidity through CD8 Co-receptor Modification: A Novel Mechanism to Enhance TCR Gene Therapy
Identification of structural and functional correlates of robust antitumour T cell responses
Manipulating T lymphocyte homing and activation for cancer immunotherapy.
Genetic Engineering Tumour Infiltrating Lymphocytes (TILs) to achieve enhanced tumour killing

Original classification

Collaborative Award in Science

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