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

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.<br><br>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.<br><br>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.<br><br><i>Thesis is embargoed until 31 July 2030.</i>