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<p>Acute myeloid leukemia&#xa0;(AML)&#xa0;cells and activated T cells rely on aerobic glycolysis for energy metabolism. The TP53-induced glycolysis and apoptosis regulator&#xa0;(TIGAR)&#xa0;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<sup>+</sup> T cell counts and raised CD4/CD8 ratio, downregulating CD44 and immune checkpoints CTLA-4, LAG-3, PD-1 on cell surface of CD8<sup>+</sup> T cells. TIGAR depletion boosted cytokine secretion (IFN-γ, perforin, granzyme B, TNF-α) by CD8<sup>+</sup> T cells and IL-2, TNF-α by CD4<sup>+</sup> 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<sup>+</sup> T cell dysfunction and induces anti-AML immunity.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月26日

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

摘要

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.