Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment

Abstract

Metabolic reprogramming and immune escape play a major role in tumorigenesis. Increasing number of studies have shown that reprogramming of glutamine metabolism is a putative determinant of the anti-tumor immune response in the tumor microenvironment (TME). Usually, the predatory uptake of glutamine by tumor cells in the TME results in the limited utilization of glutamine by immune cells and affects the anti-tumor immune response. The cell-programmed glutamine partitioning also affects the anti-tumor immune response. However, the reprogramming of glutamine metabolism in tumors modulates immune escape by regulating tumor PD-L1 expression. Likewise, the reprogramming of glutamine metabolism in the immune cells also affects their immune function. Additionally, different types of glutamine metabolism inhibitors extensively regulate the immune cells in the TME while suppressing tumor cell proliferation. Herein, we discuss how metabolic reprogramming of tumor and immune cells regulates anti-tumor immune responses, as well as functional changes in different immune cells in the context of targeting tumor glutamine metabolism, which can better explain the potential of targeting glutamine metabolism in combination with immunotherapy for cancer. Video abstract.

Keywords: Glutamine metabolism; Glutamine metabolism inhibitors; Immune response; Immunity; Reprogramming; Tumor microenvironment.

Fig. 1

Association of glutamine metabolism with tumor cells and immune cells. The competition for glutamine between tumor cells and immune cells in the TME causes glutamine deficiency, which affects the function of immune cells, including macrophages, DCs, Treg cells, neutrophils, B cells and so on (A). Cell-programmed glutamine partitioning results in the highest consumption of glutamine by tumor cells in the TME. CAFs can up-regulate their glutamine synthesis, and complement glutamine depletion in the TME by secreting glutamine into the TME (B)

Fig. 2

Reprogramming of glutamine metabolism in tumor cells and T cells and its impact on immune response. Inhibition of the glutamine transporter inhibits the differentiation of Teff cells while simultaneously promotes the differentiation of Treg cells (①). Inhibition of the GLS promotes the differentiation and effector function of Teff cells (②). Glutamine deprivation affects the differentiation of naive T cells, and up-regulates the expression of PD-L1 in tumor cells by activating the EGFR/ERK/C-Jun signaling pathway or reducing GSH levels, inhibiting SERCA activity, and then activating the NF-κB signaling pathway (③)

Fig. 3

Impact of reprogramming of glutamine metabolism in immune cells on immune response. M2 macrophages consume more glutamine, and α-KG, a metabolite of glutamine metabolism, which promote the polarization of M2 macrophages. Glutamine metabolism in M2 macrophages is essential for supporting an active TCA cycle and UDP-GlcNAc synthesis. This provides the substrate for N-glycosylation, enabling the glycosylation of M2-marked proteins, and promoting the polarization of M2 macrophages (①). Glutamine metabolism in M1 macrophages promotes the accumulation of succinate by replenishing α-KG, further improving the stability of HIF-1α, which regulates the polarization of M1 macrophages (②). Inhibition of ASCT2 and GLS in B cells reduces the production of IgG and IgM antibodies (③). Glutamine regulates neutrophil function by generating ATP and regulating the expression of components of the NADPH oxidase complex, but its pro-tumor or anti-tumor effect is unknown (④). Suppression of glutamine metabolism in NK cells inhibits its anti-tumor function (⑤)

Fig. 4

Effects of glutamine metabolism inhibitors on immune response. Glutamine antimetabolites L-DON and JHU-083 can inhibit glutamine metabolism, glycolysis, and OXPHOS in tumor cells, and comprehensively disintegrate the energy metabolism of tumors (①). Glutamine antimetabolites directly modulate the metabolism of CD8⁺CTLs to promote a long-lasting, activated, memory-like phenotype; enhance cytokine production; and inhibit exhaustion and apoptosis (②). Glutamine antimetabolites inhibit the generation and recruitment of MDSCs and induce the differentiation of MDSCs and TAMs into pro-inflammatory TAMs by suppressing the secretion of CSF3 (③). Glutamine antimetabolites inhibit the expression of IDO in tumor and myeloid derived cells; reduce the levels of kynurenine; and enhance anti-tumor immune response (④). Glutamine antimetabolites inhibit the HBP metabolic pathway; decrease the levels of hyaluronan; change the mechanical properties of the ECM; improve the immunosuppressive TME and enhance the anti-tumor immune response (⑤). Glutamine uptake inhibitor V-9302 has distinct effects on the differentiation of T cell subsets, favoring CD4⁺Th1 and CD8⁺CTL but reducing the levels of Treg cells (⑥, ⑧). Glutaminase inhibitor CB-839 enhances the activation of CD4 ⁺ Th1 and CD8⁺ CTL but suppress the differentiation of CD4⁺Th17 cells (⑦, ⑧)