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SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity

Cancer cells evade T cell-mediated killing through tumour–immune interactions whose mechanisms are not well understood(1,2). Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours(3). DC functions are orchestrated by pattern...

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Autores principales: Guo, Chuansheng, You, Zhiyuan, Shi, Hao, Sun, Yu, Du, Xingrong, Palacios, Gustavo, Guy, Cliff, Yuan, Sujing, Chapman, Nicole M., Lim, Seon Ah, Sun, Xiang, Saravia, Jordy, Rankin, Sherri, Dhungana, Yogesh, Chi, Hongbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10396969/
https://www.ncbi.nlm.nih.gov/pubmed/37407815
http://dx.doi.org/10.1038/s41586-023-06299-8
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author Guo, Chuansheng
You, Zhiyuan
Shi, Hao
Sun, Yu
Du, Xingrong
Palacios, Gustavo
Guy, Cliff
Yuan, Sujing
Chapman, Nicole M.
Lim, Seon Ah
Sun, Xiang
Saravia, Jordy
Rankin, Sherri
Dhungana, Yogesh
Chi, Hongbo
author_facet Guo, Chuansheng
You, Zhiyuan
Shi, Hao
Sun, Yu
Du, Xingrong
Palacios, Gustavo
Guy, Cliff
Yuan, Sujing
Chapman, Nicole M.
Lim, Seon Ah
Sun, Xiang
Saravia, Jordy
Rankin, Sherri
Dhungana, Yogesh
Chi, Hongbo
author_sort Guo, Chuansheng
collection PubMed
description Cancer cells evade T cell-mediated killing through tumour–immune interactions whose mechanisms are not well understood(1,2). Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours(3). DC functions are orchestrated by pattern recognition receptors(3–5), although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity(6–8), but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour–cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8(+) T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.
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spelling pubmed-103969692023-08-04 SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity Guo, Chuansheng You, Zhiyuan Shi, Hao Sun, Yu Du, Xingrong Palacios, Gustavo Guy, Cliff Yuan, Sujing Chapman, Nicole M. Lim, Seon Ah Sun, Xiang Saravia, Jordy Rankin, Sherri Dhungana, Yogesh Chi, Hongbo Nature Article Cancer cells evade T cell-mediated killing through tumour–immune interactions whose mechanisms are not well understood(1,2). Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours(3). DC functions are orchestrated by pattern recognition receptors(3–5), although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity(6–8), but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour–cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8(+) T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment. Nature Publishing Group UK 2023-07-05 2023 /pmc/articles/PMC10396969/ /pubmed/37407815 http://dx.doi.org/10.1038/s41586-023-06299-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Guo, Chuansheng
You, Zhiyuan
Shi, Hao
Sun, Yu
Du, Xingrong
Palacios, Gustavo
Guy, Cliff
Yuan, Sujing
Chapman, Nicole M.
Lim, Seon Ah
Sun, Xiang
Saravia, Jordy
Rankin, Sherri
Dhungana, Yogesh
Chi, Hongbo
SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity
title SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity
title_full SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity
title_fullStr SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity
title_full_unstemmed SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity
title_short SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity
title_sort slc38a2 and glutamine signalling in cdc1s dictate anti-tumour immunity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10396969/
https://www.ncbi.nlm.nih.gov/pubmed/37407815
http://dx.doi.org/10.1038/s41586-023-06299-8
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