Glutamine is critical for the maintenance of Type 1 Conventional Dendritic cells in normal tissue and the tumor microenvironment.

Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDC) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets – cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mTOR signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses. Overall design: In vitro FLT3L-differentiated cDCs generated from wild-type C57BL/6 mice. cDCs were differentiated in either 2 mM or 50 µM Glutamine, or in 2 mM Glutamine with 1 uM DON, and then harvested for single-cell RNAseq.