Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy

Abstract

Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor microenvironment, dysregulation of amino acid consumption in immune cells is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered amino acid metabolism is tightly linked to tumor outgrowth, metastasis, and therapeutic resistance through governing the fate of various immune cells. During these processes, the concentration of free amino acids, their membrane bound transporters, key metabolic enzymes, and sensors such as mTOR and GCN2 play critical roles in controlling immune cell differentiation and function. As such, anti-cancer immune responses could be enhanced by supplement of specific essential amino acids, or targeting the metabolic enzymes or their sensors, thereby developing novel adjuvant immune therapeutic modalities. To further dissect metabolic regulation of anti-tumor immunity, this review summarizes the regulatory mechanisms governing reprogramming of amino acid metabolism and their effects on the phenotypes and functions of tumor-infiltrating immune cells to propose novel approaches that could be exploited to rewire amino acid metabolism and enhance cancer immunotherapy.

Keywords: Amino acids; Immune cells; SLC transporters; Tumor microenvironment; mTOR.

Fig. 1

Amino acid metabolism in effector T cells. Various amino acids are transported by SLC transporters into the cytoplasm. These amino acids activate sensor proteins in the cytoplasm such as mTOR, GCN2, and Sestrin (highlighted in green bold font), directly activate the TCR-CD3 complex, or are metabolized further to affect T cell development and survival. Solid lines represent effects and reactions in T cells, and dashed lines represent uncertain effects and reactions in T cells. The arrow line represents activation and the line with a bar at the end represents inhibition. AHR Aryl hydrocarbon receptor; Ala Alanine; Arg Arginine; Asn Asparagine; BCAT Branched-chain aminotransferases; Gclc Glutamate cysteine ligase; GCN2 General control nonderepressible 2; Gln Glutamine; GSH Glutathione; HMB β-hydroxy-β-methylbutyrate; iNOS Inducible isoform of NO synthase; Kyn Kynurenine; Leu Leucine; Met Methionine; MHC Major histocompatibility complex; mTORC1 Mechanistic target of rapamycin kinase complex 1; Ser Serine; SHMT2 Mitochondrial serine hydroxymethyltransferase; SLC Solute carrier; TCR T cell receptor; Trp Tryptophan

Fig. 2

Amino acid metabolism in B cells. Several amino acids are associated with B cell function and differentiation, and threonine can further affect the differentiation and function of monocytes. The solid line represents certain effects and reactions in B cells, and the dashed line represents potential effects and reactions in B cells. The arrow line represents activation and the line with a bar at the end represents inhibition. GABA γ-aminobutyric acid; GAD Glutamate decarboxylase; Glu Glutamate; His Histidine; IgG Immunoglobulin G; IgM Immunoglobulin M; IL Interleukin; Leu Leucine; mTORC1 Mechanistic target of rapamycin kinase complex 1; SLC Solute carrier; Teff cell Effector T cell

Fig. 3

Reprogramming of amino acid metabolism in the innate immune system. In the innate immune system, various amino acids affect innate immune cell functions. The same amino acids may play different role in the homeostasis/inflammation microenvironment and tumor microenvironment. The arrow line represents activation and the line with a bar at the end represents inhibition. 3-HAA 3-hydroxyanthranilic acid; AHR Aryl hydrocarbon receptor; Arg Arginine; Arg1/2 Arginase-1/2; BCAA Branched-chain amino acids; BCAT1 branched-chain aminotransferases 1; BH4 Tetrahydrobiopterin; BTK Bruton’s tyrosine kinase; C3 Complement 3; CTLA4 Cytotoxic T-lymphocyte associated protein 4; Cys Cystine; GCN2 General control nonderepressible 2; GCN2 General control nonderepressible 2; Gln Glutamine; Glu Glutamate; GSH Glutathione; HIF Hypoxia inducible factor; IDO Indoleamine 2,3-dioxygenase; IL Interleukin; iNOS Inducible isoform of NO synthase; KMO Kynurenine 3-monooxygenase; Kyn Kynurenine; KYNU 2-amino-4-[3-hydroxyphenyl]-4-hydroxybutanoic acid; Leu Leucine; LPS Lipopolysaccharide; SLC Solute carrier; STAT3 Signal transducer and activator of transcription 3; TAM Tumor-associated macrophages; TGF Transforming growth factor; Trp Tryptophan; Tα1 Thymosin α1

Fig. 4

Amino acid competition in the TME. T cells compete with macrophages, MDSCs, and tumor cells for several amino acids, which influence the anti-tumor functions of T cells. Moreover, these cells produce kynurenine to suppress T cells, emphasizing the complexity of amino acid metabolism in the TME. The dashed line represents two lines that do not intersect. The arrow line represents activation and the line with a bar at the end represents inhibition. AHR Aryl hydrocarbon receptor; Arg Arginine; Arg1/2 Arginase-1/2; DC Dendritic cell; IDO Indoleamine 2,3-dioxygenase; iNOS Inducible isoform of NO synthase; Kyn Kynurenine; MDSC Myeloid-derived suppressor cell; Met Methionine; MTA Methylthioadenosine; PD-1 Programmed death 1; SAM S-adenosylmethionine; STAT5 Signal transducer and activator of transcription 5; TAM Tumor-associated macrophages; Trp Tryptophan