Elucidating the importance of programmed cell death -1 in modulating innate lymphoid cells within the tumour microenvironment

Abstract

Ph. D. Thesis.Programmed cell death – 1 receptor (PD-1) is an inhibitory co-receptor which is critical for immune regulation and tolerance. Following engagement with its ligands, Programmed cell death ligand (PDL)- 1 and -2, PD-1 inhibits cellular proliferation and cytokine production. Although literature has focused on T cells, emerging literature has identified PD-1 as a negative regulator of innate lymphoid cells (ILCs). ILCs are a tissue resident subset of the innate immune system which are divided into 3 groups; namely group 1 (including NK cells and ILC1s), group 2 and group 3 (including Lymphoid Tissue Inducers; LTi cells). We have demonstrated that PD-1 regulates ILC2s, whereby inhibition of PD-1 results in increased cell proliferation and cytokine production (Taylor et al., 2017). In human, all ILC subsets are capable of expressing PD-1 within the tumour (Salimi et al., 2018) though the regulation of these cells within the tumour microenvironment (TME) remains undetermined. Murine cancer models identified a unique ILC1 subset, namely Tbet+Nkp46+RORgt - ILC1s, that were found to upregulate PD-1 expression in the TME (p=0.01) and were significantly increased in the absence of PD-1 (p=0.02). Absence of PD-1 also led to the increase in cellular proliferation and cytokine production. Data indicated PD-1 may modulate the metabolic profile of ILC1 subset Tbet+NKp46+RORgt - ILC1s. Human data confirmed observations in mice, whereby human ILCs were capable of upregulating PD-1 in the presence of tumour cells and PD-1 negatively regulated cellular proliferation. Specifically, an equivalent PD-1+ subset was identified within human cutaneous squamous cell carcinoma (cSCC) tumours which was absent in patient peripheral blood mononuclear cells (PBMCs). In conclusion, PD-1 signalling specifically dampens Tbet+Nkp46+RORgt - ILCs activity within the TME highlighting a potential therapeutic target which could enhance patient responses