Understanding iNKT cell Metabolic features in GlioBlastoMa tumours to improve Immunotherapy

Project Information

ImmunoGBMet

Grant agreement ID: 101108116

DOI

10.3030/101108116

Project closed

EC signature date 12 May 2023

Start date 1 October 2023

End date 30 September 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 199 694,40

Coordinated by

THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD, OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Ireland

Periodic Reporting for period 1 - ImmunoGBMet (Understanding iNKT cell Metabolic features in GlioBlastoMa tumours to improve Immunotherapy)

Reporting period: 2023-10-01 to 2025-09-30

Summary of the context and overall objectives of the project

Glioblastoma is one of the most aggressive forms of brain cancer, with very limited treatment options and poor survival rates. In recent years, immunotherapy has brought major advances for several cancers, but these benefits have not yet translated to glioblastoma. One of the main obstacles is that these tumours create a very hostile environment for immune cells. This environment, known as the tumour microenvironment, contains large amounts of inhibitory molecules and unusual metabolic conditions that weaken the ability of immune cells to detect and eliminate cancer cells. Understanding why immune cells fail in this environment is essential for developing more effective therapies.
Among the many immune cell types that participate in anti-tumour responses, NK and NKT cells are especially interesting. However, very little is known about how these cells behave inside glioblastoma tumours, or how the metabolic conditions created by the tumour affect their function. Recent research suggests that lipids and other metabolites build up inside tumours and interfere with the metabolic pathways immune cells rely on. When these pathways are disrupted, immune cells can become dysfunctional and unable to mount a proper response.
This project set out to understand how the metabolic environment inside glioblastoma tumours alters the behaviour of immune cells, and how these alterations contribute to their reduced effectiveness. The project aimed to identify which metabolic pathways are most affected when immune cells enter the tumour. With this knowledge, the project intended to explore new strategies for engineering immune cells that are more resistant to the harsh tumour environment.
The overarching objective was to build the scientific foundation for improving immunotherapy approaches for glioblastoma. By uncovering the metabolic weaknesses imposed on NK and NKT cells and exploring ways to reinforce them, the project contributes to long-term efforts to create more durable and effective immune-based treatments for aggressive cancers. Beyond glioblastoma, the findings may also inform future strategies for boosting immune responses in other diseases where metabolism plays a critical role.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project combined ex vivo and in vivo approaches to understand how the metabolic environment of glioblastoma influences the behaviour of NKT cells and other immune populations. The work began with the development of controlled ex vivo systems to test how oxysterols — lipid-derived molecules known to accumulate in tumours — affect the function of invariant NKT (iNKT) cells. Using these models, the project examined how iNKT cells responded to oxysterols by measuring cytokine production, metabolic activity and key intracellular signalling pathways. These findings provide evidence that specific tumour-associated lipids directly contribute to weakening anti-tumour immunity.
In parallel, an orthotopic in vivo model of glioblastoma was established to study how the tumour environment shapes immune responses in a more physiological context. Using flow cytometry, the project analysed how major immune cell types, including natural killer (NK) cells and T cells, were altered within the tumour. This allowed the identification of immune features associated with tumour-induced suppression.
Together, these complementary approaches provided a multi-level view of how glioblastoma disrupts immune function.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project advances current knowledge by identifying how tumour-derived oxysterols directly impair invariant NKT (iNKT) cell function in glioblastoma, an area that was previously poorly understood. The work shows that these metabolites alter cytokine production, metabolism and signalling in iNKT cells, revealing a new mechanism of immune suppression. In parallel, analysis of NK and T cells in an orthotopic tumour model demonstrates broader metabolic immune dysfunction within the glioblastoma environment. Together, these findings highlight metabolic pathways that could be targeted to strengthen anti-tumour immunity.
The results open new possibilities for next-generation immunotherapies, including engineering immune cells to withstand suppressive metabolic cues or designing interventions that modulate tumour-associated metabolites.