Enhancing cancer immunotherapy through the identification and characterisation of novel T-regulatory cell targets

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Whilst cancer immunotherapies have seen a recent boom in their potential to treat patients with several different late-stage cancer types, the long-term response rates of even the most promising treatments such as ipilimumab and nivolumab (CTLA-4 and PD-1 checkpoint inhibitors, respectively) remain low at around 21%. A strong contributing factor to this is the immunosuppressive nature of the tumour microenvironment (TME). T-regulatory cells (Tregs) are a subset of CD4+ T cells that, under normal physiological conditions, dampen the body's immune responses to self-antigens and thus play an important part in preventing autoimmunity. However, within the TME, this regulatory phenotype can reduce the efficacy of the host's immune response against the tumour, also limiting the effectiveness of many current immunotherapies. Selectively targeting and depleting these tumour Tregs thus becomes an appealing strategy to boost the response rate of current treatments. This project aims to bioinformatically identify novel potential tumour Treg targets by filtering mouse Treg RNA-seq data for genes with suitable characteristics for a therapeutic target. Differential expression, presence on the exterior side of the cell surface and homology to human genes will be investigated to ensure genes are enriched in tumour Tregs and targetable by antibody therapy. These targets will then be tested for cell surface protein expression and evaluated against a library of Treg-binding antibodies developed by an industrial collaborator (BioInvent Intl AB) in vitro, to determine whether any bind to the enriched targets. Those that do bind will then have their binding profiles and depletion capabilities assessed, with promising antibodies then being brought forward into in vivo depletion experiments, followed by tumour therapy experiments both alone and in combination with immune checkpoint blockade.