Metabolic regulatory crosstalk between tumor microenvironment and tumor-associated macrophages

Abstract

Macrophages phagocytize pathogens to initiate innate immunity and products from the tumor microenvironment (TME) to mediate tumor immunity. The loss of tumor-associated macrophage (TAM)-mediated immune responses results in immune suppression. To reverse this immune disorder, the regulatory mechanism of TAMs in the TME needs to be clarified. Immune molecules (cytokines and chemokines) from TAMs and the TME have been widely accepted as mutual mediators of signal transduction in the past few decades. Recently, researchers have tried to seek the intrinsic mechanism of TAM phenotypic and functional changes through metabolic connections. Numerous metabolites derived from the TME have been identified that induce the cell-cell crosstalk with TAMs. The bulk tumor cells, immune cells, and stromal cells produce metabolites in the TME that are involved in the metabolic regulation of TAMs. Meanwhile, some products from TAMs regulate the biological functions of the tumor as well. Here, we review the recent reports demonstrating the metabolic regulation between TME and TAMs.

Keywords: Tumor-associated macrophage; metabolism; tumor immunotherapy; tumor microenvironment.

Figure 1

The metabolic crosstalk: from TME to TAMs. Tumor cell-derived lactic acid, succinate, α-ketoglutarate, ATP/Adenosine, PGE2 (prostaglandin E2), oleate, Retinoic acid (RA), BCKA (branched-chain ketoacids), kynurenine, POSTN (periostin), versican, sonic hedgehog and the extracellular acidosis promote the protumoral TAM formation to accelerate tumor progression. Artificially increasing HRG (histidine-rich glycoprotein) or stearic acid expression from tumor cell induce the antitumoral TAM. Metabolites from T cell to TAM are rarely identified, but activated T cell enhances IDO and SREBP1 (sterol regulatory element-binding protein 1) in TAM to facilitate tumor growth. CAF (cancer-associated fibroblast)-produced lactic acid, ADMA (asymmetric dimethyl arginine), BHB (beta-hydroxybutyrate), hyaluronan and STC1 (stanniocalcin-1) assist TAM to be protumoral. Mast cell-released LTB4 (leukotriene B4), chondroitin sulfate and tryptase/chymase guide TAM toward into tumor promoting. However, PGD2 (prostaglandin D2) from mast cell may bind DP (PGD2 receptors) on TAM and skews TAM to be antitumoral. Histamine triggers H4R (histamine H4-receptor) on macrophage into protumoral TAM, but H2R (histamine H2-receptor) into antitumoral TAM. Adipocyte-derived APN (adiponectin), leptin and A-FABP (adipose fatty acid binding protein) induce the protumoral TAM. Chemerin from adipocyte causing the phenotypic change of TAM is tumor context dependent. MCT1/4 (monocarboxylate transporter 1/4); SUCNR1 (succinate receptor1); GPCR (G protein-coupled receptors); FAO (fatty acid oxidation); P2XRs/P2YRs (P2 purinergic receptors); A2AR/A2BR (adenosine receptors); BCAA (branched-chain amino acid); HCA2 (hydroxycarboxylic acid receptor 2); LTB4R1/2 (leukotriene B4 receptor 1/2); AdipoR (adiponectin receptor); ChemR23 (chemokine-like receptor 1, CMKLR1); PIGF (placental growth factor); E-FABP (epidermal fatty acid binding protein); ICER (inducible cyclic AMP (cAMP) early repressor); CREB (cyclic AMP-responsive element binding); AHR (aryl hydrocarbon receptor); RAR (retinoid acid receptor); UCP2 (uncoupling protein 2).

Figure 2

The metabolic crosstalk: from TAMs to TME. TAM-derived cholesterol, itaconic acid, creatine and A-FABP switch its own phenotype into protumoral TAM. E-FABP (epidermal fatty acid binding protein) from TAM induces the antitumoral TAM formation. TAM-caused arginine consumption, eicosanoid and kynurenine accumulation result in immunosuppressive T cell. These effects reflect the immune microenvironment changes induced by metabolites from TAM. TAM-produced osteopontin, collagen and MMP9 (matrix metalloproteinase 9) promote tumor metastasis. Lower vitamin D-caused decreased cathelicidin in TAM and TAM-released deoxycytidine induce drug resistance. REDD1(regulated in development and DNA damage response 1)-dependent Sema4D (semaphorin 4D) secretion from TAM accelerates tumor angiogenesis. ABHD5 (abhydrolase domain-containing 5); 15-LOX2 (15-lipoxygenase-2); Irg1 (immune-responsive gene 1).