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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Format: | Article |
Language: | English |
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The Royal Society
2024-03-01
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Series: | Royal Society Open Science |
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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. |
first_indexed | 2024-04-25T00:11:21Z |
format | Article |
id | doaj.art-77818205b84c4a3a9f3ff240e817a43d |
institution | Directory Open Access Journal |
issn | 2054-5703 |
language | English |
last_indexed | 2024-04-25T00:11:21Z |
publishDate | 2024-03-01 |
publisher | The Royal Society |
record_format | Article |
series | Royal Society Open Science |
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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