PMID- 37407815 OWN - NLM STAT- MEDLINE DCOM- 20230807 LR - 20240216 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 620 IP - 7972 DP - 2023 Aug TI - SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. PG - 200-208 LID - 10.1038/s41586-023-06299-8 [doi] AB - 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. CI - (c) 2023. The Author(s). FAU - Guo, Chuansheng AU - Guo C AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - You, Zhiyuan AU - You Z AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Shi, Hao AU - Shi H AUID- ORCID: 0000-0002-2796-629X AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Sun, Yu AU - Sun Y AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Du, Xingrong AU - Du X AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Palacios, Gustavo AU - Palacios G AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Guy, Cliff AU - Guy C AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Yuan, Sujing AU - Yuan S AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Chapman, Nicole M AU - Chapman NM AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Lim, Seon Ah AU - Lim SA AUID- ORCID: 0000-0001-6560-4874 AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Sun, Xiang AU - Sun X AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Saravia, Jordy AU - Saravia J AUID- ORCID: 0000-0002-2691-501X AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Rankin, Sherri AU - Rankin S AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Dhungana, Yogesh AU - Dhungana Y AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Chi, Hongbo AU - Chi H AUID- ORCID: 0000-0002-9997-2496 AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. hongbo.chi@stjude.org. LA - eng GR - R01 AI131703/AI/NIAID NIH HHS/United States GR - R01 AI150514/AI/NIAID NIH HHS/United States GR - R37 AI105887/AI/NIAID NIH HHS/United States GR - R35 CA253188/CA/NCI NIH HHS/United States GR - R01 AI150241/AI/NIAID NIH HHS/United States GR - R01 AI140761/AI/NIAID NIH HHS/United States GR - R01 AI105887/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20230705 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Amino Acid Transport System A) RN - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors) RN - 0RH81L854J (Glutamine) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Tumor Suppressor Proteins) SB - IM CIN - Cancer Discov. 2023 Sep 6;13(9):1957. PMID: 37477403 CIN - Cell Chem Biol. 2023 Sep 21;30(9):1012-1014. PMID: 37738953 MH - *Amino Acid Transport System A/metabolism MH - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism MH - CD8-Positive T-Lymphocytes/immunology MH - *Dendritic Cells/immunology/metabolism MH - *Glutamine/metabolism MH - *Neoplasms/immunology MH - Proto-Oncogene Proteins/metabolism MH - *Signal Transduction MH - Tumor Suppressor Proteins/metabolism PMC - PMC10396969 COIS- H.C. is a consultant for Kumquat Biosciences. H.C. and C. Guo are authors of a patent application related to glutamine targeting. All other authors declare no competing interests. EDAT- 2023/07/06 01:08 MHDA- 2023/08/04 06:43 PMCR- 2023/07/05 CRDT- 2023/07/05 23:33 PHST- 2022/08/11 00:00 [received] PHST- 2023/06/08 00:00 [accepted] PHST- 2023/08/04 06:43 [medline] PHST- 2023/07/06 01:08 [pubmed] PHST- 2023/07/05 23:33 [entrez] PHST- 2023/07/05 00:00 [pmc-release] AID - 10.1038/s41586-023-06299-8 [pii] AID - 6299 [pii] AID - 10.1038/s41586-023-06299-8 [doi] PST - ppublish SO - Nature. 2023 Aug;620(7972):200-208. doi: 10.1038/s41586-023-06299-8. Epub 2023 Jul 5.