Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors

Abstract

It has been appreciated for nearly 100 years that cancer cells are metabolically distinct from resting tissues. More recently understood is that this metabolic phenotype is not unique to cancer cells but instead reflects characteristics of proliferating cells. Similar metabolic transitions also occur in the immune system as cells transition from resting state to stimulated effectors. A key finding in immune metabolism is that the metabolic programs of different cell subsets are distinctly associated with immunological function. Further, interruption of those metabolic pathways can shift immune cell fate to modulate immunity. These studies have identified numerous metabolic similarities between cancer and immune cells but also critical differences that may be exploited and that affect treatment of cancer and immunological diseases.

Keywords: T cell; antitumor immunity; glycolysis; inflammation; macrophage; mitochondria; tumor metabolism; tumor microenvironment.

Figure 1. Glycolysis and pentose phosphate pathway (PPP) in biosynthesis and immune function

Glycolysis and the PPP provide biosynthetic intermediates and reducing power for cell growth and proliferation. In immune cells, select branches provide key metabolites for immune function such as reducing power for the synthesis of reactive oxygen species (ROS) and antioxidants in phagocytic cells and for phospholipid synthesis in dendritic cells. In contrast, suppression of PPP by carbohydrate kinase-like protein (CARKL) induces an anti-inflammatory M2 macrophage phenotype. Hexosamine biosynthesis pathway provides substrates for glycosylation of lipids and proteins important for Treg and M2 macrophage lineages. In rapidly proliferating cells such as T cells and M1 macrophages, glycolysis-derived pyruvate is reduced to lactate to regenerate NAD+ and exported out of the cell. DHAP, dihydroxyacetone phosphate; GLUT1, glucose transporter 1; MCT1, monocarboxylate transporter 1; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PEP, phosphoenol pyruvate; PKM2, pyruvate kinase M2; TAG, triacyl glycerol.

Figure 2. TCA cycle in biosynthesis and epigenetics

The major TCA cycle inputs from glycolysis, glutaminolysis and fatty acid oxidation provide substrates for ATP production, NADPH generation (via malate and isocitrate) and biosynthetic intermediates for nucleotide, fatty acid and cholesterol synthesis. In M1 macrophages, the break in the TCA cycle after citrate ensures it is fluxed to lipid synthesis and production of antimicrobial itaconate. Breakage of the TCA cycle at succinate dehydrogenase (SDH) in M1 macrophages and in SDH-deficient cancer cells, or fumarate hydratase (FH)-deficient cancer cells leads to accumulation of succinate and/or fumarate, which inhibits α-ketoglutarate-dependent prolyl hydroxylases leading to transcription factor HIF1α stabilization. Apart from metabolic reprogramming, in macrophages this promotes transcription of il1b gene. ACC1, acetyl-CoA carboxylase 1; ACLY, ATP-citrate lyase; ACSS1/2 acetyl-CoA synthetase 1/2; CPT1, carnitine palmitoyltransferase 1; FH, fumarate hydratase; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; SDH, succinate dehydrogenase.

Figure 3. Nitrogen metabolism in cell proliferation and immune function

Purine and pyrimidine nucleotide synthesis requires glutamine and aspartate-derived nitrogen in proliferating cancer cells and effector T cells. Arginine metabolism provides polyamines and nitric oxide for proliferating cells. Arginine is differentially utilized by inflammatory M1 macrophages for NO synthesis while the anti-inflammatory M2 macrophages divert arginine to polyamine and hydroxyproline synthesis, inhibiting NO production. ASS1, argininosuccinate synthetase 1; CAD1/2, carbamoyl phosphate synthetase 1/2; IMP, inosine monophosphate; PPAT, phosphoribosyl pyrophosphate amidotransferase; PRPP, phosphoribosyl pyrophosphate.

Figure 4. Proliferative metabolic programming and signaling exhibited by effector T cells, inflammatory macrophages and cancer cells versus the catabolic metabolism and signaling in Treg, M2 macrophages, memory T cells and quiescent cancer cells

(A) M1 macrophages, effector T cells and cancer cells are characterized by biosynthetic metabolism to support proliferation and anabolism with high rates of glycolysis and glutaminolysis for the synthesis of proteins, nucleic acids and lipids. In contrast, Treg, M2 macrophages, memory T cells and quiescent cancer cells are primarily characterized by catabolic metabolism and utilization of fatty acid oxidation for ATP synthesis. (B) Activation of growth factor receptors leads to Akt-mediated upregulation of glucose uptake and glycolytic flux and promotes lipid synthesis. Proliferative signals and metabolic hues are balanced with biosynthetic metabolism by mTORC1, which orchestrates nucleotide and protein synthesis via ribosomal protein S6 kinase with progression through the cell cycle via 4EBP1. Transcription factors Myc, HIF1α and SREBPs mediate glutamine and glucose metabolism and promote lipid and cholesterol synthesis. These pathways are opposed by PTEN and AMPK which inhibit PI3K and mTORC1 signaling and promote fatty acid oxidation, autophagy and transcriptional co-activator PGC1α-mediated mitochondrial biogenesis. PPP, pentose phosphate pathway.

Figure 5. Metabolic enzymes in immune function

Metabolic enzymes directly impact immunity. When glycolysis is low, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) binds the 3’untranslated region of ifng gene, suppressing its transcription. In contrast, lactate dehydrogenase A (LDHA) promotes cytoplasmic accumulation of acetyl-CoA, a substrate for histone acetylation which promotes transcription of ifng gene important in Th1-mediated immune responses. Enolase 1 is involved in splicing of the Treg signature transcription factor FOXP3 into FOXP3-E2 splice variant, while hexokinase 1 (HK1) promotes caspase-dependent cleavage of IL1β into its active form. Breakage of the TCA cycle at succinate dehydrogenase (SDH) in M1 macrophages leads to accumulation of succinate and production of mitochondrial ROS, inhibiting α-ketoglutarate-dependent prolyl hydroxylases that leads to stabilization of transcription factor HIF1α. In M1 macrophages this promotes transcription of il1b gene. α-kg, α-ketoglutarate; PDH, pyruvate dehydrogenase.