SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity

Chuansheng Guo, Zhiyuan You, Hao Shi, Yu Sun, Xingrong Du, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole M. Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana and Hongbo Chi ()
Additional contact information
Chuansheng Guo: St. Jude Children’s Research Hospital
Zhiyuan You: St. Jude Children’s Research Hospital
Hao Shi: St. Jude Children’s Research Hospital
Yu Sun: St. Jude Children’s Research Hospital
Xingrong Du: St. Jude Children’s Research Hospital
Gustavo Palacios: St. Jude Children’s Research Hospital
Cliff Guy: St. Jude Children’s Research Hospital
Sujing Yuan: St. Jude Children’s Research Hospital
Nicole M. Chapman: St. Jude Children’s Research Hospital
Seon Ah Lim: St. Jude Children’s Research Hospital
Xiang Sun: St. Jude Children’s Research Hospital
Jordy Saravia: St. Jude Children’s Research Hospital
Sherri Rankin: St. Jude Children’s Research Hospital
Yogesh Dhungana: St. Jude Children’s Research Hospital
Hongbo Chi: St. Jude Children’s Research Hospital

Nature, 2023, vol. 620, issue 7972, 200-208

Abstract: Abstract Cancer cells evade T cell-mediated killing through tumour–immune interactions whose mechanisms are not well understood1,2. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours3. DC functions are orchestrated by pattern recognition receptors3–5, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity6–8, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06299-8

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