Cancer management and research · 2026
TNFAIP3 Reprograms T Cell Exhaustion and Restores Anti-Leukemia Immunity in Acute Myeloid Leukemia.
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Li Yanhong, Wu Hongxia, Bai Jun, Peng Xiaohuan, Chen Yue, Zhang Jinping, Zhang Liansheng, Li Lijuan
Аннотация
PURPOSE: Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is associated with profound immune dysfunction. T-cell exhaustion is a major mechanism of immune evasion in AML; however, the key molecular regulators driving this process remain unclear. This study aimed to identify immunoregulatory genes associated with T cell exhaustion in AML and define their functional roles.
PATIENTS AND METHODS: Single-cell RNA sequencing (scRNA-seq) data from patients with AML and healthy donors were integrated to identify genes associated with T-cell exhaustion. TNFAIP3 was identified as a candidate hub gene and subsequently validated in peripheral T cells from 24 AML patients and 12 healthy donors using qRT-PCR and Western blotting. Functional studies were performed using lentivirus-mediated TNFAIP3 overexpression in patient-derived CD4+ and CD8+ T-cells. Apoptosis, immune checkpoint expression, cytokine production, and NF-κB signaling activity were assessed using pathway enrichment analyses.
RESULTS: scRNA-seq analysis revealed widespread immune remodeling in AML, with TNFAIP3 consistently downregulated in AML T cells. Reduced TNFAIP3 expression was confirmed at both the mRNA and protein levels in patients with AML. TNFAIP3 overexpression in CD4+ and CD8+ T cells attenuates apoptosis, reduces the expression of the immune checkpoint molecules PD-L1 and TIM-3, and promotes a pro-inflammatory cytokine profile characterized by increased IFN-γ and TNF-α production. Mechanistically, these effects were associated with the suppression of NF-κB signaling and enrichment of pathways related to immune synapse formation and T-cell receptor signaling.
CONCLUSION: Our findings demonstrate that TNFAIP3 is a critical regulator of T cell dysfunction and exhaustion in AML. Downregulation of TNFAIP3 contributes to impaired anti-leukemic immunity, whereas its restoration enhances T-cell survival and effector function. TNFAIP3 therefore represents a promising therapeutic target for immune-based interventions aimed at restoring T-cell-mediated immunity in AML.
PATIENTS AND METHODS: Single-cell RNA sequencing (scRNA-seq) data from patients with AML and healthy donors were integrated to identify genes associated with T-cell exhaustion. TNFAIP3 was identified as a candidate hub gene and subsequently validated in peripheral T cells from 24 AML patients and 12 healthy donors using qRT-PCR and Western blotting. Functional studies were performed using lentivirus-mediated TNFAIP3 overexpression in patient-derived CD4+ and CD8+ T-cells. Apoptosis, immune checkpoint expression, cytokine production, and NF-κB signaling activity were assessed using pathway enrichment analyses.
RESULTS: scRNA-seq analysis revealed widespread immune remodeling in AML, with TNFAIP3 consistently downregulated in AML T cells. Reduced TNFAIP3 expression was confirmed at both the mRNA and protein levels in patients with AML. TNFAIP3 overexpression in CD4+ and CD8+ T cells attenuates apoptosis, reduces the expression of the immune checkpoint molecules PD-L1 and TIM-3, and promotes a pro-inflammatory cytokine profile characterized by increased IFN-γ and TNF-α production. Mechanistically, these effects were associated with the suppression of NF-κB signaling and enrichment of pathways related to immune synapse formation and T-cell receptor signaling.
CONCLUSION: Our findings demonstrate that TNFAIP3 is a critical regulator of T cell dysfunction and exhaustion in AML. Downregulation of TNFAIP3 contributes to impaired anti-leukemic immunity, whereas its restoration enhances T-cell survival and effector function. TNFAIP3 therefore represents a promising therapeutic target for immune-based interventions aimed at restoring T-cell-mediated immunity in AML.