Immunosuppressive Immature Myeloid Cell Generation Is Controlled by Glutamine Metabolism in Human Cancer

Abstract

Tumor-associated myeloid cells are one of the prominent components of solid tumors, serving as major immune regulators for the tumor microenvironment (TME) and an obstacle for immune-checkpoint blocking (ICB) therapy. However, it remains unclear how metabolic processes regulate the generation of suppressive myeloid cells in the TME. Here, we found that hematopoietic precursor cells are enriched in the tissues of several types of human cancer and can differentiate into immature myeloid cells (IMC). Tumor-infiltrating IMCs are highly immunosuppressive, glycolytic, and proliferative, as indicated by high levels of M-CSFR, Glut1, and Ki67. To elucidate the role of metabolism in regulating the generation of IMCs, we induced suppressive IMCs from hematopoietic precursor cells with GM-CSF and G-CSF in vitro. We found that the generation of suppressive IMCs was accompanied by increased glycolysis, but not affected by glucose deprivation due to alternative catabolism. Generation of IMCs relied on glutaminolysis, regardless of glucose availability. Glutamine metabolism not only supported the expansion of IMCs with glutamine-derived a-ketoglutarate but also regulated the suppressive capacity through the glutamate-NMDA receptor axis. Moreover, inhibition of glutaminase GLS1 enhanced the therapeutic efficacy of anti-PD-L1 treatment, with reduced arginase 1 þ myeloid cells, increased CD8 þ , IFNg þ and granzyme B þ T cells, and delayed tumor growth in an ICB-resistant mouse model. Our work identified a novel regulatory mechanism of glutamine metabolism in controlling the generation of suppressive IMCs in the TME.

Contribution of ROS and metabolic status to neonatal and adult CD8+ T cell activation

“…The microenvironment of the neonatal lymphocytes shows high levels of the enzyme arginase [42], which would limit Arginine, which in turn would affect the glutamine available for synthesis de novo of glutathione [31]. The correct balance of these metabolic activities is crucial for T cell function, as exemplified by infiltrating lymphocytes in a tumor microenvironment in which ROS, glutaminase and arginase contribute to lower the activation potential of immune cells [15–17, 22, 23].…”

“…Arginase and adenosine are metabolic inhibitors associated with a lack of T cell responsiveness in cancer [11–14]. Indeed, the pathways of arginine and glutamine metabolism are implicated in tolerance to tumors and are considered as therapeutic targets [15–17].…”

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…GLUL was also found to enhance HCC cell migration and invasion both in vitro and in vivo, and higher GLUL level independently predicted a poorer prognosis in HCC patients (103). In addition, Wu et al suggested that glutamine metabolism could support highly immunosuppressive tumor-infiltrating immature myeloid cells with glutamine-derived a-ketoglutarate, and could also regulate their suppressive capacity through the glutamate-NMDA receptor axis, in which inhibiting GLS1 improved the efficacy of anti-PD-L1 treatment, with decreased Arginase1+ myeloid cells, increased CD8+, IFNg+, as well as granzyme B+ T cells, and delayed tumor growth in an immunotherapy-resistant mouse model (104). Johnson et al demonstrated that GLS1 plays an important role in T cell activation and subset specification (105).…”

Energy metabolism manipulates the fate and function of tumour myeloid-derived suppressor cells

“…2 Among the key energy metabolism pathways listed above, glycolysis and the PPP occur in the cytosol; the TCA cycle, OXPHOS, and FAO are limited to the mitochondria; and glutaminolysis progresses in both the cytosol and mitochondria. 3,4 Cancer cells rely on glycolysis to produce ATP even under aerobic conditions, which is known as the Warburg effect. Aerobic glycolysis is a central requirement for meeting the bioenergetic and biosynthetic needs of rapidly proliferating cancer cells.…”