Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration

Area of Science:

• Immunology
• Systems Biology
• Metabolic Engineering

Background:

• The tumour-immune microenvironment (TIME) critically influences tumour progression and immune evasion.
• Immune cell metabolism within TIME affects nutrient availability and anti-tumour responses.
• Metabolic reprogramming offers a strategy to shift the immune response towards a pro-inflammatory state.

Purpose of the Study:

• To propose immunomodulatory mechanisms based on metabolic reprogramming.
• To develop a comprehensive system-level model integrating signalling, metabolism, and regulatory processes in TIME.
• To identify novel strategies for enhancing anti-tumour immunity and suppressing tumour activity.

Main Methods:

• Utilized regulatory flux balance analysis (FBA) modelling.
• Integrated signalling, metabolism, and regulatory processes.
• Incorporated time lags between signalling and regulatory events.

Main Results:

• Identified specific metabolic alterations to enhance immune response and suppress tumour activity.
• Demonstrated that altering succinate and oxaloacetate exchange between glioma and macrophages boosts pro-inflammatory responses.
• Showed that inhibiting T-cell glutamate uptake disrupts glioma's antioxidant mechanisms and reprograms metabolism.
• Found that combining AMP-activated protein kinase (AMPK) activation with glutamate uptake inhibition is highly effective for restoring T-cell function.

Conclusions:

• A systems-level understanding of metabolism and gene regulation is crucial for promoting immune cell recovery from tumour dominance.
• Metabolic reprogramming presents a promising avenue for developing novel cancer immunotherapies.
• Targeting specific metabolic pathways and nutrient exchange offers potential to overcome tumour-induced immune suppression.