Active Cancer Infection & Immunity

Regulatory T cell-mediated suppression of cytotoxic T cells activated with ImmTACs

Funder Wellcome Charity-funded
Recipient organisation University of Bristol
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

A patient's own immune system can sabotage a promising new cancer therapy before it gets a chance to work. This project tackles a specific blind spot in cancer immunotherapy. Immune-mobilising monoclonal T cell receptors against cancer (ImmTACs) are synthetic molecules designed to force a patient's killer T cells to attack tumours. But tumours are often infiltrated by regulatory T cells (Tregs), which normally prevent autoimmune attacks. In the tumour environment, Tregs suppress the very killer cells that ImmTACs are trying to activate. It is not known how Tregs interfere with ImmTAC function, or whether the effect depends on how many killer cells are present or what other cells are in the tumour. The researchers will rebuild the tumour environment in a dish, mixing Tregs, killer T cells, and tumour cells, then add ImmTACs to see exactly how Tregs blunt the attack. This is fundamental science: it will reveal a mechanism of immune suppression that current therapies ignore. If successful, the work could guide the design of combination treatments—for example, depleting Tregs before giving an ImmTAC—or help identify which patients are most likely to benefit from these therapies.

View original technical description
Regulatory T cells (Tregs) are suppressive immune cells that are critical in maintaining immune homeostasis and self-tolerance, limiting autoimmunity and dampening inflammatory responses. Tregs can be highly enriched in the tumour microenvironment (TME) and enrichment is associated with poor patient prognosis. Tregs contribute to the immunosuppressive nature of the TME. The TME impairs the function of key anti- tumour effector cells, prominently cytotoxic T lymphocytes (CTL). CTL are activated by recognition of tumour-associated or neo-antigens, presented by Major Histocompatibility Complex (MHC) molecules on the tumour surface. Such recognition can be therapeutically enhanced with Immune mobilising monoclonal T cell receptors (TCR) against cancer (ImmTACs). ImmTACs are synthetic, bispecific T cell engagers composed of an affinity- enhanced TCR recognising an MHC-tumour associated peptide complex, linked to an activating scFv fragment of an antibody against the TCR subunit CD3ε. In vitro, ImmTACs trigger killing and cytokine secretion by CTL. It is poorly understood how Tregs modulate T cell engager function and alter therapeutic efficacy, but it is likely context-dependent, e.g. driven by CTL abundance and TME composition. This project will use an in vitro TME reconstitution approach to examine how Tregs affect ImmTAC-mediated CTL activation.

View the original record at the funder ↗

Researchers

Alice Hayward-Wills (EPMC Awardee)

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Original classification

PhD Studentship (Basic)

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