Amino Acids and Their Transporters in T Cell Immunity and Cancer Therapy

Abstract

Metabolism reprogramming is critical for both cancer progression and effective immune responses in the tumor microenvironment. Amino acid metabolism in different cells and their cross-talk shape tumor immunity and therapy efficacy in patients with cancer. In this review, we focus on multiple amino acids and their transporters, solute carrier (SLC) members. We discuss their involvement in regulation of immune responses in the tumor microenvironment and assess their associations with cancer immunotherapy, chemotherapy, and radiation therapy, and we review their potential as targets for cancer therapy. We stress the necessity to understand individual amino acids and their transporters in different cell subsets, the molecular intersection between amino acid metabolism, and effective T cell immunity and its relevance in cancer therapies.

Keywords: CD8(+) T cell; amino acid; cancer; checkpoint blockade; immunotherapy; metabolism; solute carriers.

Figure 1.. Roles of amino acids and their transporters in T cell function

TCR engagement and co-stimulation affect multiple pathways and upregulate amino acid transporters, SLCs in T cells, thereby increasing amino acid uptake. This supports T cell activation, proliferation, and differentiation. Some amino acids and their transporters are required for T cell activation, differentiation, and function: glutamine (Gln), alanine (Ala), serine (Ser), leucine (Leu), methionine (Met), arginine (Arg), cysteine (Cys) and cystine (Cys-Cys). Examples are depicted in the figure.

Figure 2.. Effects of methionine metabolism on T cell function and tumor immunity

Methionine metabolism generates a universal methyl donor S-adenosyl-methionine (SAM). Tumor cells express high levels of SLC43A2 and consume methionine in the tumor microenvironment. This results in insufficient methionine and SAM for T cells - thus causing loss of CD8⁺ T cell H3K79me2 and STAT5 expression and function, and impairing H3K4me3 and Th17 polarization.

Figure 3.. Role of arginine and Try-Kyn metabolisms in tumor immune evasion

Arginine (Arg) is transported by SLC7A2. Intracellular Arg metabolism results in extracellular Arg depletion and NO production. Arg deficiency impairs and NO inhibits T cell function. Trp is transported by SLC3A2 and SLC7A5 or SLC7A8. Trp is catalyzed by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO) to become kynurenine (Kyn). Trp-Kyn metabolism results in extracellular Trp depletion and Kyn accumulation, subsequently causing T cell inhibition. Arginine deiminase (ADI-PEG20) degrades arginine. PEG-KYNase degrades Kyn. Small inhibitors that target key enzymes in Arg and Trp-Kyn metabolic pathways are listed in red.

Figure 4.. Immune-directed amino acid metabolism reprogramming in cancer therapy

Checkpoint receptors, including CTLA-4 and PD-1, negatively regulate T cell activation in part by limiting the uptake and catabolism of amino acids. Checkpoint blockade may reprogram T cell amino acid metabolism and improve T cell function. Immunotherapy-induced IFNγ downregulates the expression of cystine (Cys-Cys) transporter, SLC7A11, in cancer associated fibroblasts - resulting in a decrease in cysteine (Cys) and glutathione (GSH) for tumor cells. Decreased intracellular glutathione in tumor cells augments intracellular cisplatin accumulation and sensitizes platin-based chemotherapy. IFNγ also suppresses cystine uptake by downregulating SLC7A11 and SLC3A2 in cancer cells, resulting in an increase in tumor lipid peroxidation and ferroptosis, and synergizing immunotherapy, chemotherapy, and radiation therapy.