Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy

Abstract

Tumor-infiltrating myeloid cells are a prominent pro-tumorigenic immune cell population that limit host anti-tumor immunity and present a significant obstacle for many cancer immunotherapies. Targeting the mechanisms regulating myeloid cell function within the tumor microenvironment may overcome immunotherapy resistance in some cancers. Recent discoveries in the emerging field of immunometabolism reveal that the metabolic profiles of intratumoral myeloid cells are rewired to adapt to the nutrition-limited tumor microenvironment, and this shapes their pro-tumor phenotypes. Interestingly, metabolic modulation can shift these myeloid cells toward the immune-stimulating anti-tumor phenotype. In this review, we will highlight the roles of specific metabolic pathways in the activation and function of myeloid cells, and discuss the therapeutic value of metabolically reprogramming myeloid cells to augment and improve outcomes with cancer immunotherapy.

Keywords: immunometabolism; immunotherapy; myeloid cells; myeloid-derived suppressor cells; tumor-associated dendritic cells; tumor-associated macrophages; tumor-associated neutrophils; tumor-infiltrating myeloid cells.

FIGURE 1

The metabolic state and immune cells in tumor microenvironment. The altered metabolic activity of tumor cells creates an environment lacking oxygen, glucose and amino acid, and enriched with fatty acids. To adapt to this nutrient challenge, myeloid cells such as tumor-associated dendritic cells (TADC), myeloid-derived suppressor cells (MDSC), tumor-associated neutrophils (TAN), and tumor-associated macrophage (TAM) alter their metabolic program.

FIGURE 2

The metabolic features of MDSCs. The tumor-infiltrating MDSCs upregulate glycolysis pathway to support their expansion, while promoting amino acid and fatty acid metabolism to support their immunosuppressive function. “↑” indicates “increase.” HK, hexokinase; PFK1, Phosphofructokinase 1; PKM2, Pyruvate kinase isozymes M1/M2; NMDAR, N-methyl-d-aspartate receptor; LDHA, Lactate dehydrogenase A; GLS, Glutaminase; CPT1A, Carnitine Palmitoyltransferase 1A; HADHA, Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Alpha; ACADM, Acyl-CoA Dehydrogenase Medium Chain.

FIGURE 3

The metabolic features of TAM. The tumor-infiltrating TAMs upregulate glycolysis pathway to regulate their migration and pro-metastatic capability, while promote amino acid and fatty acid metabolism to support their immunosuppressive function. “↑” indicates “increase.” PDK1, Pyruvate Dehydrogenase Kinase 1; PGK1, Phosphoglycerate Kinase 1; GCK, Glucokinase; HK2, Hexokinase 2; ENO1, Enolase 1; PKM2, Pyruvate kinase isozymes M1/M2; GLUT1, Glucose transporter 1; GLUL, Glutamate-Ammonia Ligase; GS, Glutamine synthetase.

FIGURE 4

The metabolic features of TADC. The tumor-infiltrating TADC upregulate fatty acid metabolism to support their immunosuppressive function while the role amino acid and glycolysis pathway in not yet clear. “↑” indicates “increase.” CPT1A, Carnitine Palmitoyltransferase 1A.

FIGURE 5

The metabolic feature of TAN. Most metabolic pathways in TAN are not well-defined, except that FATP2-mediated fatty acid metabolism plays an important role in their pro-tumorigenic phenotype. “↑” indicates “increase.” FATP2, Fatty acid transport protein 2.

FIGURE 6

The interaction of metabolism and epigenetics. The intermediate metabolites in metabolic pathway play a vital role in regulating the epigenetic modification, especially histone acetylation and methylation. The histone acetylation requires acetyl-CoA generated from TCA cycle in mitochondria as an essential substrate. On the other hand, the histone demethylation needs a-KG from TCA cycle as important cofactor of the Jumonji C domain-containing histone demethylases (JMJDs).