SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity

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.

Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy

“…91 Notably, it was recently revealed that glutamine was required for cDC1 function via the solute carrier family member SLC38A2, which could not only mediate the glutamine competition between tumor cells and DCs, but also trigger the antitumoral immunity. 92 This research also suggests the important roles of multifunctional metabolic enzymes in tumor immunity. Thus, tumor cell metabolism-derived nutrient depletion and toxic metabolites can not only promote intrinsic immunoevasion of tumor cells but also impair the antitumor function of T cells and antigen presentation by DCs; however, the role of tumor cell metabolism underlying adaptive immunity escape requires further investigation.…”

“…Hypoxia can influence DC differentiation, antigen uptake, as well as migration ability . Notably, it was recently revealed that glutamine was required for cDC1 function via the solute carrier family member SLC38A2, which could not only mediate the glutamine competition between tumor cells and DCs, but also trigger the antitumoral immunity . This research also suggests the important roles of multifunctional metabolic enzymes in tumor immunity.…”

Sphingomyelin is a prospective metabolic immune checkpoint for natural killer cells

“…Within the tumour microenvironment, nutritional and metabolic competition among various cell types is apparent 4 . This often results in tumour cells having the upper hand, leaving immune cells at a disadvantage and thereby restricting their access to essential nutrients.…”

Role of solute carrier transporters in regulating dendritic cell maturation and function

“…SLC38A2 is widely expressed by various immune cells, among which DCs have the highest levels. A recent study focused on glutamine-mediated intercellular crosstalk between cancer cells and DCs in TME [56]. They found that intratumoral supplementation of glutamine enhanced cancer immunotherapy by strengthening the accumulation and effector function of CD8 + T cells and promoting antigen-presenting function of DCs.…”