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| Status |
Public on May 24, 2023 |
| Title |
SLC38A2 and glutamine signaling in cDC1 dictate anti-tumor immunity [scRNA-Seq 1] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Cancer cells evade T-cell-mediated killing through poorly understood mechanisms of tumour–immune interactions. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1), mediate T-cell priming and therapeutic efficacy against tumours. Besides pattern recognition receptors (PRRs), how DC functions are shaped by other environmental cues remains incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients impact DC function or innate–adaptive cell communication is largely unresolved. Here, we establish glutamine as an intercellular metabolic checkpoint to mediate tumour–cDC1 crosstalk and license cDC1 functionality for activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T-cell immunity, and also overcomes therapeutic resistance to checkpoint blockade and T-cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1 compete for glutamine uptake via transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid for promoting cDC1 function, by signalling via FLCN to impinge upon TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner, and phenocopies SLC38A2 deficiency by abrogating anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1 that underpins tumour immunoevasion, and reveal glutamine acquisition and signalling in cDC1 as limiting events for DC activation and putative targets for cancer treatment.
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| Overall design |
wild-type and Flcn∆DC mice (n = 2 per genotype) were challenged with MC38 cells. CD45+ cells and DC (CD45+CD64−CD11c+MHC-II+) in the tumour tissues were sorted at 15 d after tumour challenge and mixed at a 2:1 ratio.
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| Contributor(s) |
Guo C, Sun Y, Shi H, Chi H |
| Citation(s) |
37407815 |
| |
| Submission date |
Jul 31, 2022 |
| Last update date |
Jul 24, 2023 |
| Contact name |
Hongbo Chi |
| E-mail(s) |
hongbo.chi@stjude.org
|
| Organization name |
St Jude Children's Research Hospital
|
| Department |
Immunology
|
| Street address |
262 Danny Thomas Place
|
| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE210155 |
SLC38A2 and glutamine signaling in cDC1 dictate anti-tumor immunity |
|
| Relations |
| BioProject |
PRJNA864056 |
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