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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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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. |
format | Online Article Text |
id | pubmed-10396969 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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