THE EFFECTS OF MANNOSE IN SOLID TUMOURS AND ITS POTENTIAL AS AN ENHANCER OF CAR-T-CELL THERAPY

Student thesis: Phd

Abstract

Despite success with B-cell malignancy, CAR-T-cells have yet to make an impact in the clinic against solid cancer. Multiple factors make the solid tumour microenvironment a hostile place for T cells. Tumour and myeloid-derived cells are avid competitors with T cells for nutrients and create toxic waste due to their increased metabolic activity, contributing to T cell exhaustion and malfunction. Notably, tumour microenvironments are glucose-depleted, hypoxic, and acidic. In exploring interventions that selectively antagonise tumour cell metabolism, we find that supplementation with the hexose mannose may boost T cell function. We utilised various in vitro techniques for assessing cell function and proliferation capacities to understand the mechanism by which mannose alters cell biology. By using in vivo models, we aimed to assess the efficacy of combining both therapies. Our results confirmed that mannose suppresses the viability of a range of cultured human cancer cells by 1) creating an ATP deficit, resulting in their death by pyroptosis, and 2) inducing cell cycle arrest and senescence. Intriguingly, and in contrast, T cells treated with mannose upregulate key glycolytic enzymes, maintain lactate secretion even at low glucose concentrations, and did not lose viability or proliferative capacity. Preliminary in vivo data corroborates the in vitro findings concerning the effects of mannose on tumour cells. However, in vivo data did not provide enough evidence to support combining with CAR-T-cell therapy. Mannose is a simple, well-tolerated, inexpensive intervention that alters tumour cell biology without affecting T cell function and biology. Our results highlight that mannose can potentially boost CAR-T-cell and TIL activity in the solid tumour microenvironment. However, more research is needed to further validate the benefits, if any, of combining these therapeutics.
Date of Award6 Jan 2025
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorAdam Hurlstone (Supervisor), Fiona Thistlethwaite (Supervisor) & Amaya Viros Usandizaga (Supervisor)

Keywords

  • Mannose
  • Immunotherapy
  • Cancer
  • Car T cell

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