Project ID CM-HD2023_37

ThemeCM-HD

Co Supervisor 1A Inflammation Biology / Immunology and Microbial Sciences / FOLSMWebsite

Co Supervisor 1B Inflammation Biology / Immunology and Microbial Sciences / FOLSMWebsite

Immunometabolism in tolerance and inflammation: lessons from checkpoint inhibitor therapy for solid tumours

Immune checkpoint inhibition (CPI) has revolutionised the landscape in cancer treatment. However, there are two major limitations to these treatments: firstly, and due to their immune-stimulatory nature, they may cause severe toxicity that mimics autoimmune diseases; secondly, their efficacy is limited in solid tumours, due to the ability of the tumour microenvironment (TME) to supress the immune response. An important factor driving this immunosuppression are immune-metabolic maladaptations conditioned by TME.

Our work has discovered that changes in cholesterol metabolism can switch the inflammatory profile of immune cells with great specificity. We hypothesise that changes in cholesterol metabolism are important in driving the anti-tumour response and the therapeutic efficacy of CPI treatment.

This project will focus on discovering whether manipulations of cholesterol metabolism can switch the exhausted phenotype towards more productive anti-tumour immune responses. Furthermore, we will interrogate the biobank generated by our clinical trial PAIR, a longitudinal cohort (>130 patients already recruited) of CPI-treated cancer patients, to investigate further the immunometabolic changes and immune activation related to outcome and adverse events. These discoveries might pave the way for future translational manipulations.

Our labs combine expertise in T-cell immunology, cancer biology, inflammation and immunometabolism, providing a great environment for this project. You will develop and utilise skills in primary human cell culture, functional immune and metabolic assays and molecular biology, becoming an expert in multicolour flow cytometry, RNA-seq, molecular cloning and qPCR techniques.

Objectives:
1. Y1. Manipulating cholesterol metabolism to modulate T-cell immune exhaustion in vitro, assessing its possible role as adjuvant therapy to CPI.
2. Y2. Unravelling the molecular mechanism whereby cholesterol metabolism regulates T-cell exhaustion.
3. Y3. Identify these molecular pathways and their contribution to toxicity in the PAIR biobank.

One representative publication from each co-supervisor:

• Perucha E, Melchiotti R, Bibby J, Wu W, Stensgaard Frederiksen, Roberts CA, Hall Z, LeFriec G, Robertson KA, Gammeltoft Gerwien J, Taams LS, Griffin JL, de Rinaldis E, van Baarsen LGM, Kemper K, Ghazal P, Cope AP. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 effector T cells. Nat Comms 2019;10:498.

• Patel AJ, Willsmore ZN, Khan N, Richter A, Naidu B, Drayson MT, Papa S, Cope AP, Karagiannis SN, Perucha E, Middleton GW. Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade. Nat Comms 2022;13:3148.