Can Kras driven metabolic reprogramming in advanced lung cancer alter T cell phenotypes and functions?

Abstract

Immunotherapy (IO) has become an increasingly popular treatment regimen for lung cancer patients over the past decade. However, predicting who will or will not respond and understanding drivers of resistance are vital to capitalise on the effectiveness of IO treatment. Advanced lung cancers have distinct reprogramming of glucose metabolism, driven by Krasmutant specific copy gains. We postulated that the changes this imposes on the metabolic tumour microenvironment (TME) will alter T cell activation and function, resulting in poor response to IO. The goal of this project was to define how metabolic reprogramming might do this, and if targeting enhanced glucose metabolism in tumour cells has potential to enhance efficacy of IO in advanced tumours.

Using a combination of in vitro and in vivo approaches, we profiled the impact of metabolic reprogramming on the TME using multi-omic methodologies. We defined the subsequent effect on the functional T cell landscape by high-parameter flow cytometry, immunohistochemical and metabolic analyses, and evaluated the consequences for IO response in advanced GEMM models in vivo.

Here, we confirm that advanced lung tumours with enhanced glucose metabolism display poor response to anti-PD-1 treatment. Mechanistically, we can demonstrate that increased glucose metabolism in advanced tumour cells significantly alters the metabolic and cytokine profiles of the TME that can actively block T cell proliferation. Inhibition of this metabolic axis, both genetically and pharmacologically, reverts this phenotype. Furthermore, by comprehensively analysing the T cell landscape we see changes in recruitment, localisation, co-stimulation, and activation of distinct T cell subtypes that together promote a more immunosuppressive, “pro-tumour” landscape. We evaluated metabolic strategies to target tumour cell metabolic reprogramming and revert this TME stress, with the hope to improve response to IO therapy in advanced lung cancer models.

In this thesis I demonstrate that metabolic reprogramming in cancer cells directly impacts the TME at both a metabolic and cytokine level. These changes correlate with a dramatic impact on T cell subsets at multiple levels – recruitment, infiltration, activation, function, and checkpoint expression – ultimately driving a tolerant TME that in turn dampens response to IO treatment. Reverting this metabolic change in cancer cells has the potential to restore T cell function and enhance IO response, but this must be CD8+ T cell sparing to be effective.

Thesis is embargoed until 31 July 2030.

Date of Award	Jul 2025
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Emma Kerr (Supervisor), Beckie Ingram (Supervisor) & Donna Small (Supervisor)