Glutamine Deprivation Promotes the Generation and Mobilization of MDSCs by Enhancing Expression of G-CSF and GM-CSF

Abstract

Solid tumors are often challenged by hypoxic and nutrient-deprived tumor microenvironments (TME) as tumors progress, due to limited perfusion and rapid nutrient consumption. While cancer cells can demonstrate the ability to survive in nutrient-deprived conditions through multiple intrinsic alterations, it is poorly understood how nutrient-deprived cancer cells co-opt the TME to promote cancer cell survival and tumor progression. In the present study, we found that glutamine deprivation markedly potentiated the expression of G-CSF and GM-CSF in mouse mammary cancer cells. The IRE1α-JNK pathway, which is activated by glutamine starvation, was found to be important for the upregulation of these cytokines. G-CSF and GM-CSF are well-known facilitators of myelopoiesis and mobilization of hematopoietic progenitor cells (HPC). Consistently, as tumors progressed, we found that several myeloid HPC compartments were gradually decreased in the bone marrow but were significantly increased in the spleen. Mechanistically, the HPC-maintaining capacity of the bone marrow was significantly impaired in tumor-bearing mice, with lower expression of HPC maintaining genes (i.e., CXCL12, SCF, ANGPT1, and VCAM1), and reduced levels of mesenchymal stem cells and CXCL12-producing cells. Furthermore, the mobilized HPCs that displayed the capacity for myelopoiesis were also found to accumulate in tumor tissue. Tumor-infiltrating HPCs were highly proliferative and served as important sources of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. Our work has identified an important role for glutamine starvation in regulating the expression of G-CSF and GM-CSF, and in facilitating the generation of immunosuppressive MDSCs in breast cancer.

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis

“…Metabolically reprogrammed tumor cells compete with immune cells for nutrients and release metabolites into the microenvironment, which inhibit the function of antitumor immune cells; thus, blocking the abnormal metabolism of tumor cells may be a potential way to improve the efficacy of immunotherapy. Previous studies have reported that in breast cancer, glutamine metabolism alterations increased the secretion of G-CSF and GM-CSF, then recruited MDSC to promote tumor progression [ 39 ]. The enhanced glutamine uptake influenced the composition of the immune cell infiltrates and was significantly associated with upregulated PDL1 expression as well as poor survival outcomes in breast cancer [ 40 ].…”

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

“…Low glutamine levels may affect the differentiation of MDSCs and contribute to these expanded populations in severe COVID-19, but the experimental results are inconsistent. Some studies reported that low glutamine inhibited the differentiation of MDSCs [ 84 , 85 ], while others revealed that glutamine deprivation promoted the generation of MDSCs [ 86 ]. In a murine arthritis model, the inhibition of glutaminolysis suppressed the differentiation of M-MDSCs, but promoted the expansion of G-MDSCs [ 87 ].…”

Myeloid-Derived Suppressor Cells Alleviate Renal Fibrosis Progression via Regulation of CCL5-CCR5 Axis

“…However, whether they can achieve similar efficacy in renal fibrosis remains unclear. A recent study has reported that enhanced G-CSF and GM-CSF expression promotes MDSC generation and migration (12,44), indicating that G-CSF and GM-CSF are both efficient for inducing MDSC expansion. However, although G-CSF is more commonly used in clinical settings, GM-CSF is well accepted for in vitro MDSC induction because it can induce both MDSC phenotypes (CD11b + Ly6G i n t Ly6C l o w and CD11b + Ly6G i n t Ly6C l o w populations) in a balanced manner.…”