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

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.