MondoA–Thioredoxin-Interacting Protein Axis Maintains Regulatory T-Cell Identity and Function in Colorectal Cancer Microenvironment

Background & AimsThe metabolic features and function of intratumoral regulatory T cells (Tregs) are ambiguous in colorectal cancer. Tumor-infiltrating Tregs are reprogrammed to exhibit high glucose-depleting properties and adapt to the glucose-restricted microenvironment. The glucose-responsive transcription factor MondoA is highly expressed in Tregs. However, the role of MondoA in colorectal cancer-infiltrating Tregs in response to glucose limitation remains to be elucidated.MethodsWe performed studies using mice, in which MondoA was conditionally deleted in Tregs, and human colorectal cancer tissues. Seahorse and other metabolic assays were used to assess Treg metabolism. To study the role of Tregs in antitumor immunity, we used a subcutaneous MC38 colorectal cancer model and induced colitis-associated colorectal cancer in mice by azoxymethane and dextran sodium sulfate.ResultsOur analysis of single-cell RNA sequencing data of patients with colorectal cancer revealed that intratumoral Tregs featured low activity of the MondoA–thioredoxin-interacting protein (TXNIP) axis and increased glucose uptake. Although MondoA-deficient Tregs were less immune suppressive and selectively promoted T-helper (Th) cell type 1 (Th1) responses in a subcutaneous MC38 tumor model, Treg-specific MondoA knockout mice were more susceptible to azoxymethane-DSS–induced colorectal cancer. Mechanistically, suppression of the MondoA-TXNIP axis promoted glucose uptake and glycolysis, induced hyperglycolytic Th17-like Tregs, which facilitated Th17 inflammation, promoted interleukin 17A-induced of CD8+ T-cell exhaustion, and drove colorectal carcinogenesis. Blockade of interleukin 17A reduced tumor progression and minimized the susceptibility of MondoA-deficient mice to colorectal carcinogenesis.ConclusionsThe MondoA-TXNIP axis is a critical metabolic regulator of Treg identity and function in the colorectal cancer microenvironment and a promising target for cancer therapy. The metabolic features and function of intratumoral regulatory T cells (Tregs) are ambiguous in colorectal cancer. Tumor-infiltrating Tregs are reprogrammed to exhibit high glucose-depleting properties and adapt to the glucose-restricted microenvironment. The glucose-responsive transcription factor MondoA is highly expressed in Tregs. However, the role of MondoA in colorectal cancer-infiltrating Tregs in response to glucose limitation remains to be elucidated. We performed studies using mice, in which MondoA was conditionally deleted in Tregs, and human colorectal cancer tissues. Seahorse and other metabolic assays were used to assess Treg metabolism. To study the role of Tregs in antitumor immunity, we used a subcutaneous MC38 colorectal cancer model and induced colitis-associated colorectal cancer in mice by azoxymethane and dextran sodium sulfate. Our analysis of single-cell RNA sequencing data of patients with colorectal cancer revealed that intratumoral Tregs featured low activity of the MondoA–thioredoxin-interacting protein (TXNIP) axis and increased glucose uptake. Although MondoA-deficient Tregs were less immune suppressive and selectively promoted T-helper (Th) cell type 1 (Th1) responses in a subcutaneous MC38 tumor model, Treg-specific MondoA knockout mice were more susceptible to azoxymethane-DSS–induced colorectal cancer. Mechanistically, suppression of the MondoA-TXNIP axis promoted glucose uptake and glycolysis, induced hyperglycolytic Th17-like Tregs, which facilitated Th17 inflammation, promoted interleukin 17A-induced of CD8+ T-cell exhaustion, and drove colorectal carcinogenesis. Blockade of interleukin 17A reduced tumor progression and minimized the susceptibility of MondoA-deficient mice to colorectal carcinogenesis. The MondoA-TXNIP axis is a critical metabolic regulator of Treg identity and function in the colorectal cancer microenvironment and a promising target for cancer therapy.