Journal Article

Blockade of TIGAR prevents CD8+ T cell dysfunction and elicits anti-AML immunity

Sun, Qian, Qian, Sixuan, Xu, Pei, Hu, Xingfei, Fang, Yiran, Li, Kening, Wang, Rong, Liu, Wenjie, Zhou, Wanting, Cui, Jialin, Xu, Cheng, Zhong, Shiyang, Hong, Ming

2025

Overview

Acute myeloid leukemia (AML) cells and activated T cells rely on aerobic glycolysis for energy metabolism. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and protects AML cells from apoptosis. Preliminary studies suggest that combining TIGAR inhibition with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) may offer a therapeutic strategy for AML. However, it remains unclear whether silencing TIGAR can enhance T cell function and thereby improve AML prognosis. This study aims to investigate whether TIGAR silencing in host can eliminate AML cells and rejuvenate dysfunctional T cells with mouse models. TIGAR knockout mice on the C57BL/6J background were generated and AML mouse models were established through intravenous injection of C1498 cells. We found that TIGAR depletion enhanced CD8 + T cell counts and raised CD4/CD8 ratio, downregulating CD44 and immune checkpoints CTLA-4, LAG-3, PD-1 on cell surface of CD8 + T cells. TIGAR depletion boosted cytokine secretion (IFN-γ, perforin, granzyme B, TNF-α) by CD8 + T cells and IL-2, TNF-α by CD4 + T cells, improving cytotoxicity against AML cells, proliferation, and reducing apoptosis. TIGAR suppression in host with 2-DG prolonged AML mouse survival, decreased tumor burden, and leukemic infiltration. TIGAR suppression restored thymic T cell development and peripheral immune balance. Single-cell RNA sequencing analysis also revealed that high TIGAR expression influences the glycolysis pathway, and correlates with markers of T cell exhaustion. This study indicates that blocking TIGAR prevents CD8 + T cell dysfunction and induces anti-AML immunity.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V,Springer
• Subject: Acute myeloid leukemia / Animal models / Animals / Apoptosis / Apoptosis Regulatory Proteins / Cancer Research / CD223 antigen / CD4 antigen / CD44 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell culture / Cell Line, Tumor / Cell proliferation / Cell surface / CTLA-4 protein / Cytotoxicity / Disease Models, Animal / Energy metabolism / Glucose / Glycolysis / Granzyme B / Humans / Immune checkpoint / Immunity / Immunology / Knockout mice / Leukemia, Myeloid, Acute - immunology / Leukemia, Myeloid, Acute - pathology / Lymphocytes / Lymphocytes T / Medical prognosis / Medicine / Medicine & Public Health / Metastases / Mice / Mice, Inbred C57BL / Mice, Knockout / Oncology / PD-1 protein / Perforin / Phosphoric Monoester Hydrolases / Sequence analysis / Single-cell RNA sequencing / T-lymphocytes / Thymus / TP53-induced glycolysis and apoptosis regulator / Tumor necrosis factor-α