TH1 cytokines induce senescence in AML

Hashimoto, Hisayoshi; Güngör, Derya; Krickeberg, Naomi; Schmitt, Johanna; Doll, Larissa; Schmidt, Marina; Schleicher, Sabine; Criado-Moronati, Elvira; Schilbach, Karin

doi:10.1016/j.leukres.2022.106842

Cited by 6 publications

(7 citation statements)

References 40 publications

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“…Hashimoto et al. reported that PRAME-specific T H 1 cells induced senescence and cell cycle arrest in AML cell lines and fresh patient-derived AML blasts through the combination of IFN-γ and TNF-α ( 98 ). Yao et al.…”

Section: Adoptive Immunotherapymentioning

confidence: 99%

Targeting PRAME for acute myeloid leukemia therapy

Yang,

Chen,

et al. 2024

Front. Immunol.

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Despite significant progress in targeted therapy for acute myeloid leukemia (AML), clinical outcomes are disappointing for elderly patients, patients with less fit disease characteristics, and patients with adverse disease risk characteristics. Over the past 10 years, adaptive T-cell immunotherapy has been recognized as a strategy for treating various malignant tumors. However, it has faced significant challenges in AML, primarily because myeloid blasts do not contain unique surface antigens. The preferentially expressed antigen in melanoma (PRAME), a cancer-testis antigen, is abnormally expressed in AML and does not exist in normal hematopoietic cells. Accumulating evidence has demonstrated that PRAME is a useful target for treating AML. This paper reviews the structure and function of PRAME, its effects on normal cells and AML blasts, its implications in prognosis and follow-up, and its use in antigen-specific immunotherapy for AML.

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Section: Adoptive Immunotherapymentioning

confidence: 99%

Targeting PRAME for acute myeloid leukemia therapy

Yang,

Chen,

et al. 2024

Front. Immunol.

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“…Similar to solid tumors ( 233 – 235 ), immune responses to neoplastic antigens ( 99 – 102 ) and stress in response to HPC damage ( 95 – 97 ) establish a chronic inflamed BME ( 93 , 94 , 236 , 237 ). The inflamed BME enhances sensitivity to exogenous antigen stimulation ( 52 , 66 , 67 ) and accelerates apoptotic death in leukemic ( 95 , 96 , 238 , 239 ) and normal ( 95 , 96 , 142 , 143 ) HPCs, which are the common clinical and laboratory features of AA and low-risk MDS ( 39 , 40 , 49 , 240 ) (as schematized in Figure 2 ).…”

Section: Potential Antileukemic Mechanism In Ahfmentioning

confidence: 99%

“…From this point of view, AHF and MNs have complex intrinsic relationships, and some patients with definitively diagnosed AA may be hMDS ( 39 , 40 , 324 , 325 ) or hAML ( 102 , 232 ). The absence of overt leukemic hematopoiesis in AHF likely results from the small number of nucleated cells available for identification of aplasia and leukemic blasts due to severe BM hypoplasia and a preferential attack on transformed HPCs by autoimmune CTLs and their secretion of hematopoietic inhibitory mediators ( 238 , 239 , 259 – 262 ). Indeed, neutropenia is a common preleukemic presentation in MNs, and in a significant proportion of MDS patients, neutropenia can be a solitary hematological abnormality that persists for many years ( 241 , 242 ).…”

Section: Reversion Of the Immune-exhausted State By Th1 Responses And...mentioning

confidence: 99%

“…A reasonable explanation for this short remission duration is that inflammatory stress-powered antileukemic activities can simultaneously repress normal ( 54 – 57 ) and malignant ( 245 – 254 ) hematopoiesis, which results in BM hypoplasia/aplasia with the infiltration of autoimmune lymphocytes and an increase in inflammatory intensity ( 34 , 35 ). The absence of leukemic blasts may be due to the preferential repression of malignant proliferation ( 238 , 239 , 259 , 260 ) and the small number of nucleated blood cells available for the identification of dysplastic features ( 232 , 240 , 324 , 325 ). Following the effective treatment of underlying infections, inflammatory stress-mediated antileukemic activities are mitigated, which leads to the simultaneous proliferation of normal and leukemic hematopoieses and transient clinical remission ( 33 – 35 ) due to the prolonged proliferative cycle of damaged HPCs ( 334 – 336 ).…”

Section: Decreased Inflammatory Strength Facilitates Leukemic Transfo...mentioning

confidence: 99%

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When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

Zhao,

Ju,

Xiu

et al. 2024

Front. Immunol.

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Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%–15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.

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“…The induction of senescence by IFN-γ and TNF-α has been described in several cancer forms such as breast cancer, rhabdomyosarcoma, and primary melanoma or sarcoma [ 17 ]. Recently, the induction of senescence has also been shown in AML cells by secretion of Th1 cytokines through tumor-specific T-cells [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Th1 cytokines in pediatric acute lymphoblastic leukemia

Schober,

Rottenberger,

Hilz

et al. 2023

Cancer Immunol Immunother

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Immune milieus play an important role in various types of cancer. The present study focuses on the effect of Th1 cytokines on pediatric acute lymphoblastic leukemia (ALL). The reaction of ALL cell lines and patient-derived xenografts (PDX) to the most important Th1 cytokines TNF-α (tumor necrosis factor alpha) and IFN-γ (interferon gamma) is analyzed and correlated with the respective cytokine receptors and the intracellular signaling molecules. ALL cell lines and ALL PDX display a great heterogeneity in cell death after incubation with TNF-α and IFN-γ. Several samples show a dose-dependent and additive induction of cell death by both cytokines; others do not react at all or even display an increased viability. Apoptosis is the main type of cell death induced by Th1 cytokines in ALL cells. Over all leukemia cells analyzed, IFN-γ receptor (IFNGR) shows a higher expression than both TNF-receptors, resulting in higher phosphorylation of STAT1 (signal transducer and activator of transcription) compared to phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) in the TNF pathway. The activation of STAT1 correlates with the amount of cell death after stimulation with Th1 cytokines. TNF-α and IFN-γ lead to heterogeneous reactions in ALL cell lines and ALL PDX but are able to induce cell death by apoptosis in the majority of ALL blasts. The correlation of a high expression of IFNGR and following activation of STAT1 with cell death indicates an important role for IFN-γ signaling in this setting.

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TH1 cytokines induce senescence in AML

Cited by 6 publications

References 40 publications

Targeting PRAME for acute myeloid leukemia therapy

Targeting PRAME for acute myeloid leukemia therapy

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

Th1 cytokines in pediatric acute lymphoblastic leukemia

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