Project ID CM-HD2024_18


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Department of Medical & Molecular GeneticsWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, St John’s Institute of DermatologyWebsite

The anti-tumour role of interleukin-36 in ovarian cancer

Interleukin-36α/β/γ (IL-36) are cytokines that play an important role in skin inflammation. These molecules have also been implicated in anti-tumour immunity, as their expression is inversely correlated with the progression of lung and ovarian cancer. While the mechanisms underlying these effects remain poorly understood, we observed that IL-36 treatment of M2 macrophages downregulates immunosuppressive molecules and upregulates co-stimulatory receptors.

The aim of this study is therefore i) to demonstrate that IL-36 reprograms M2 macrophages towards a pro-inflammatory, anti-tumour phenotype; ii) to validate the therapeutic potential of IL-36 in ovarian serous carcinoma (OV). This will be achieved by:

1. Characterising the effects of IL-36 on M2 macrophage function (Year 1-2)
The student will determine how IL-36 treatment influences the cytotoxic and immune regulatory activity of M2-like macrophages isolated from the ascites of OV patients. They will also investigate whether IL-36 can potentiate the effects of existing therapeutics by repeating their experiments in the presence of the immune checkpoint inhibitor pembrolizumab.

2. Characterising the transcriptional states of IL-36 treated OV macrophages (Year 2-3)
OV macrophages stimulated with IL-36 and/or pembrolizumab will be profiled by single-cell RNA-seq. The student will then: i) determine whether IL-36/pembrolizumab treated macrophages are transcriptionally more similar to M1 or M2 macrophages; ii) apply a variety of computational methods to identify the transcriptional activators and dynamic cell states that underlie macrophage phenotype shifts.

3. Validating the effects of macrophage phenotypic shifts on OV survival (Year 4)
The student will derive transcriptional signatures identifying the M1-like macrophage states induced by IL-36 (IL36_M1). They will then analyse publicly available OV RNA-seq data, infer the abundance of IL36_M1 populations and correlate it to tumour progression and patient survival.

This work will allow the student to validate the therapeutic potential of IL-36 and acquire a broad range of laboratory and computational skills.

Representative Publications

1. McCluskey D, Benzian-Olsson N, Mahil SK, Hassi NK, Wohnhaas CT; APRICOT and PLUM study team, Burden AD, Griffiths CE, Ingram JR, Levell NJ, Parslew R, Pink AE, Reynolds NJ, Warren RB, Visvanathan S, Baum P, Barker JN, Smith CH, Capon F. Single-cell analysis implicates Th17 to Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis. J Allergy Clin Immunol. 2022 150:882-893; doi: 10.1016/j.jaci.2022.04.027 2. Catapano M, Vergnano M, Romano M, Mahil SK, Choon SE, Burden AD, Young HS, Carr IM, Lachmann HJ, Lombardi G, Smith CH, Ciccarelli FD, Barker JN, Capon F. Interleukin-36 promotes systemic Type-I IFN responses in severe forms of psoriasis. J Invest Dermatol, 2020 140:816-826; doi: 10.1016/j.jid.2019.08.444 3. Mahil SK, Catapano M, Di Meglio P, Dand N, Ahlfors H, Carr IM, Smith CH, Trembath RC, Peakman M, Wright J, Ciccarelli F, Barker JN, Capon F. An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target. Science Translational Medicine, 2017 9:eaan2514; doi: 10.1126/scitranslmed.aan2514
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