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

Tumour-immune microenvironment (TIME) is pivotal in tumour progression and immunoediting. Within TIME, immune cells undergo metabolic adjustments impacting nutrient supply and the anti-tumour immune response. Metabolic reprogramming emerges as a promising approach to revert the immune response towar...

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Main Authors: Mudita Shukla, Rupa Bhowmick, Piyali Ganguli, Ram Rup Sarkar
Format: Article
Language:English
Published: The Royal Society 2024-03-01
Series:Royal Society Open Science
Subjects:
Online Access:https://royalsocietypublishing.org/doi/10.1098/rsos.231574
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author Mudita Shukla
Rupa Bhowmick
Piyali Ganguli
Ram Rup Sarkar
author_facet Mudita Shukla
Rupa Bhowmick
Piyali Ganguli
Ram Rup Sarkar
author_sort Mudita Shukla
collection DOAJ
description Tumour-immune microenvironment (TIME) is pivotal in tumour progression and immunoediting. Within TIME, immune cells undergo metabolic adjustments impacting nutrient supply and the anti-tumour immune response. Metabolic reprogramming emerges as a promising approach to revert the immune response towards a pro-inflammatory state and conquer tumour dominance. This study proposes immunomodulatory mechanisms based on metabolic reprogramming and employs the regulatory flux balance analysis modelling approach, which integrates signalling, metabolism and regulatory processes. For the first time, a comprehensive system-level model is constructed to capture signalling and metabolic cross-talks during tumour–immune interaction and regulatory constraints are incorporated by considering the time lag between them. The model analysis identifies novel features to enhance the immune response while suppressing tumour activity. Particularly, altering the exchange of succinate and oxaloacetate between glioma and macrophage enhances the pro-inflammatory response of immune cells. Inhibition of glutamate uptake in T-cells disrupts the antioxidant mechanism of glioma and reprograms metabolism. Metabolic reprogramming through adenosine monophosphate (AMP)-activated protein kinase (AMPK), coupled with glutamate uptake inhibition, was identified as the most impactful combination to restore T-cell function. A comprehensive understanding of metabolism and gene regulation represents a favourable approach to promote immune cell recovery from tumour dominance.
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spelling doaj.art-77818205b84c4a3a9f3ff240e817a43d2024-03-13T11:46:39ZengThe Royal SocietyRoyal Society Open Science2054-57032024-03-0111310.1098/rsos.231574Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level explorationMudita Shukla0Rupa Bhowmick1Piyali Ganguli2Ram Rup Sarkar3Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory , Pune, Maharashtra, IndiaChemical Engineering and Process Development Division, CSIR-National Chemical Laboratory , Pune, Maharashtra, IndiaChemical Engineering and Process Development Division, CSIR-National Chemical Laboratory , Pune, Maharashtra, IndiaChemical Engineering and Process Development Division, CSIR-National Chemical Laboratory , Pune, Maharashtra, IndiaTumour-immune microenvironment (TIME) is pivotal in tumour progression and immunoediting. Within TIME, immune cells undergo metabolic adjustments impacting nutrient supply and the anti-tumour immune response. Metabolic reprogramming emerges as a promising approach to revert the immune response towards a pro-inflammatory state and conquer tumour dominance. This study proposes immunomodulatory mechanisms based on metabolic reprogramming and employs the regulatory flux balance analysis modelling approach, which integrates signalling, metabolism and regulatory processes. For the first time, a comprehensive system-level model is constructed to capture signalling and metabolic cross-talks during tumour–immune interaction and regulatory constraints are incorporated by considering the time lag between them. The model analysis identifies novel features to enhance the immune response while suppressing tumour activity. Particularly, altering the exchange of succinate and oxaloacetate between glioma and macrophage enhances the pro-inflammatory response of immune cells. Inhibition of glutamate uptake in T-cells disrupts the antioxidant mechanism of glioma and reprograms metabolism. Metabolic reprogramming through adenosine monophosphate (AMP)-activated protein kinase (AMPK), coupled with glutamate uptake inhibition, was identified as the most impactful combination to restore T-cell function. A comprehensive understanding of metabolism and gene regulation represents a favourable approach to promote immune cell recovery from tumour dominance.https://royalsocietypublishing.org/doi/10.1098/rsos.231574tumour–immune interactionmetabolic reprogrammingsignalling-metabolic cross-talkssystem modelling
spellingShingle Mudita Shukla
Rupa Bhowmick
Piyali Ganguli
Ram Rup Sarkar
Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level exploration
Royal Society Open Science
tumour–immune interaction
metabolic reprogramming
signalling-metabolic cross-talks
system modelling
title Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level exploration
title_full Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level exploration
title_fullStr Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level exploration
title_full_unstemmed Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level exploration
title_short Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level exploration
title_sort metabolic reprogramming and signalling cross talks in tumour immune interaction a system level exploration
topic tumour–immune interaction
metabolic reprogramming
signalling-metabolic cross-talks
system modelling
url https://royalsocietypublishing.org/doi/10.1098/rsos.231574
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AT piyaliganguli metabolicreprogrammingandsignallingcrosstalksintumourimmuneinteractionasystemlevelexploration
AT ramrupsarkar metabolicreprogrammingandsignallingcrosstalksintumourimmuneinteractionasystemlevelexploration