Graham P. Lobel

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 – cDC1 and cDC2, 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 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. One Sentence Summary Type 1 conventional dendritic cells require glutamine to maintain their number in non-lymphoid tissue. Significance Immune evasion is a key hallmark of cancer; however, the underlying pathways are diverse, tumor-specific and not fully elucidated. Many tumor cells avidly import glutamine to support their anabolic needs, creating a glutamine-deficient tumor microenvironment (TME). Herein, using mouse models of soft tissue sarcomas, we show that glutamine depletion in TME leads to reduced type 1 conventional dendritic cells – a cell type that is critical for adaptive immune responses. This work is a paradigm for how tumor cell metabolism can regulate anti-tumor immune responses and will be foundational to future efforts targeting glutamine metabolism for cancer immunotherapy.

Supplementary Figure S4 from RALDH1 Inhibition Shows Immunotherapeutic Efficacy in Hepatocellular Carcinoma

Supplementary Figure S6 from RALDH1 Inhibition Shows Immunotherapeutic Efficacy in Hepatocellular Carcinoma

Legends for supplementary figures and tables.

Safetyscreen assay for C86 performed at eurofins.

Supplementary Figure S7 from RALDH1 Inhibition Shows Immunotherapeutic Efficacy in Hepatocellular Carcinoma

Supplementary Figure S2 from RALDH1 Inhibition Shows Immunotherapeutic Efficacy in Hepatocellular Carcinoma

Table comparing various key pharmacokinetic parameters (Assay, left column) between C-91 and C-86.

Supplementary Figure S6 from RALDH1 Inhibition Shows Immunotherapeutic Efficacy in Hepatocellular Carcinoma