Project: Sensing of tumour cells by engineered gamma-delta T-cell receptors
This project involves genetic engineering of human T cells, flow cytometry, and tumour-killing assays. The outcome of this study will create a solid basis for obtaining the next generation of γδ T cell-based cancer treatments.
Image: Human gamma-delta (γδ) T cells become activated in response to microbial and cancer-derived phosphorylated antigens, aka phosphoantigens. Our group elucidated that two cell-surface butyrophilin (BTN) protein members known as BTN2A1 and BTN3A1 work together in activating a γδ T cell receptor and initiate a potent immune response.
Gamma-delta (γδ) T cells are a critically important component of the immune system. They are often enriched in non-lymphoid tissues and respond rapidly to infection by producing inflammatory cytokines, proliferating, and acquiring cytotoxicity potential. Unlike alpha-beta (αβ) T cells, which react primarily to antigenic peptides in the context of major histocompatibility complex (MHC), most γδ T cells in humans respond to small phosphorylated non-peptide molecules called ‘phosphoantigens’. However, the molecular mechanism underpinning this recognition has been a longstanding mystery. We have recently discovered that two surface proteins belonging to the butyrophilin family are critical and enable γδ T cells to respond to phosphoantigen metabolites¹.
We have engineered high-affinity gamma-delta T-cell receptor candidates that induce potent γδ T cell activation in vitro via enhanced sensitivity to phosphoantigens. We hypothesize that these receptors confer a superior ability to sense and kill human tumours. This project aims to introduce these engineered receptors into cytotoxic CD8+ T cells to enable them to target cancer cell lines. The candidate will test and evaluate the efficacy of a wide panel of engineered T-cell receptors against an array of tumour targets to establish their clinical potential.
¹Marc Rigau et al. Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells. Science. 2020 Feb 7;367(6478):eaay5516.
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We are interested in gamma-delta (γδ) T cells, which are a vital component of the immune system and respond to many pathogens and cancer. Unlike their alpha-beta (CD4 and CD8) T cell counterparts, γδ T cells respond rapidly to infectious cues and act as a bridge between the innate and adaptive immune compartments. They are also potent killers of tumour cells, and there have been over ten clinical trials attempting to harness their immunotherapeutic potential. Our funding supports exploring the fundamental mechanisms that underpin γδ T-cell immunity, as well as developing novel γδ T cell-based immunotherapeutics.
Uldrich Group Current Projects
Sensing of tumour cells by engineered gamma-delta T-cell receptors
PhD/MPhil, Master of Biomedical Science, Honours