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 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.

Automated summary

Cancer cells evade T cell-mediated killing through unknown mechanisms. Dendritic cells, especially type-1 conventional DCs, play a crucial role in T cell priming and therapeutic efficacy against tumors. The function of dendritic cells is orchestrated by pattern recognition receptors, but other signals involved are not fully defined. Nutrients have been identified as emerging mediators of adaptive immunity, but their impact on dendritic cell function and communication between innate and adaptive immune cells is still unclear.