Immune escape and immunotherapy of acute myeloid leukemia

Vago, Luca; Gojo, Ivana

doi:10.1172/jci129204

Cited by 218 publications

(174 citation statements)

References 188 publications

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“…The above results indicated that analyzing AML patients' survival sorely relies on dysregulated immune genes expression and subsequently impaired immune activation is not that convincing. The role immunity system played in the AML tumor microenvironment is too complicated to be simpli ed into different gene [26,27,28]. So, we took different in ltration of various immune cells into concern as many studies have reported that the fraction of in ltrated immune cells in the tumor microenvironment is so unique that could be regarded as patients' instinct feature to predict tumor progression [29,30].…”

Section: Discussionmentioning

confidence: 99%

Construction of Immune-Related Prognostic Signatures in Acute Myeloid Leukemia

Liu

et al. 2020

Preprint

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Background: Acute Myeloid Leukemia (AML) is characterized as a type of hematological malignancy with poor survival. Accumulated evidence showed that dysregulated immune activities contribute to the pathogenesis of AML and accelerate the development of chemotherapy resistance. Thus, we aimed to construct prognostic signatures based on patients’ immune features to sort out the high-risk group and to identify survival-related checkpoint molecules as potential therapeutic targets.Methods: In the current study, we developed two prognostic signatures based on immune genes and infiltrated fraction of immune cells, respectively, using a least absolute shrinkage and selection operator model, and Cox regression analysis on 415 samples obtained from TCGA and GEO databases. Results: We found the optimum strategy for predicting patients’ survival is combined using these two prognostic immune-related signatures. Through our established signatures, we classified patients into Favorable Risk group and Poor Risk group, who showed significantly different OS and DFS. We further demonstrated the checkpoint molecules’ profile in different risk groups. Conclusions: we constructed a powerful prognostic tool here to help classify high-risk patients in early-stage, who may benefit from additional immune therapies by targeting identified checkpoint molecules.

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Section: Discussionmentioning

confidence: 99%

Construction of Immune-Related Prognostic Signatures in Acute Myeloid Leukemia

Liu

et al. 2020

Preprint

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“…Associated with follicular lymphoma patient survival 6 , 7 CXC-Chemokine receptor 2 (IL8RB) CXCR2_Ex3-1010 rs1126580 G Associated with CXCR2 and CXCR1 levels in whole blood (GTEx). Associated with shorter survival in diffuse large B-cell lymphoma and susceptibility to bile duct cancer 8 , 9 Interleukin 12 alpha (IL12A) IL12A_Ex7 + 277 rs568408 A Binding motifs for TFE and SIX5 Interleukin 12 beta (IL12B) IL12B_Ex8 + 159 (+1188) rs3212227 C Associated with risk of solid tumours and survival of follicular lymphoma patients 5 , 10 Interleukin 13 (IL13) IL13_-1069 rs1800925 T Associated with susceptibility to glioma, glioblastoma multiforme and CRC and an increased risk of leukopenia in metastatic renal cell carcinoma patients. Regulome score 2b 11 – 13 IL13_Ex4 + 98 rs20541 T Associated with susceptibility to multiple cancers including NHL, CRC and glioma.…”

Section: Material Subjects and Methodsmentioning

confidence: 99%

“…Furthermore, it is increasingly evident that host immunity might also be implicated in AML risk and survival 5 . AML blasts activate immunosuppressive mechanisms to evade the immune system whereas immune response changes induced by the gut microbiota can also influence the antileukaemic effects of immune cells 6 .…”

Section: Introductionmentioning

confidence: 99%

“…Sequencing studies identified genes frequently mutated in AML, some of which predict poor prognosis ( NPM1 wt / FLT3-ITD high , RUNX1 , ASXL1 and TP53 ) 4 . Furthermore, it is increasingly evident that host immunity might also be implicated in AML risk and survival 5 . AML blasts activate immunosuppressive mechanisms to evade the immune system whereas immune response changes induced by the gut microbiota can also influence the anti-leukaemic effects of immune cells 6 .…”

Section: Introductionmentioning

confidence: 99%

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Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

et al. 2020

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The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13 rs1295686A/A genotype had an increased risk of AML (P Corr = 0.0144) whereas carriers of the VEGFA rs25648T allele had a decreased risk of developing the disease (P Corr = 0.00086). In addition, we found an association of the IL8 rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (P Corr = 0.072). Functional experiments suggested that the effect of the IL13 rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8 rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

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“…Tumor-infiltrating T lymphocytes (TILs) are present in many human cancers and play a crucial role in the recognition and elimination of tumor cells [ 3 , 4 ]. A number of immune evasion mechanisms orchestrated by tumors specifically inhibit T cell immunity, such as accumulating T regulatory suppressor cell populations and repolarization of the immune response [ 5 , 6 , 7 ]. The number of successful immune-based therapies for various solid tumors has surged in the past decade.…”

Section: Introductionmentioning

confidence: 99%

Impact of Bone Marrow miR-21 Expression on Acute Myeloid Leukemia T Lymphocyte Fragility and Dysfunction

Agha

Rouas

Najar

et al. 2020

Cells

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Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy in which antitumor immunity is impaired. The therapeutic management of AML requires understanding the mechanisms involved in the fragility and immune dysfunction of AML T lymphocytes. Methods: In this study, T lymphocytes from healthy donors (HD) and AML patients were used. Extracellular vesicles (EVs) from leukemic cells were screened for their microRNA content and impact on T lymphocytes. Flow cytometry, transcriptomic as well as lentiviral transduction techniques were used to carry out the research. Results: We observed increased cell death of T lymphocytes from AML patients. EVs from leukemia myeloid cell lines harbored several miRNAs, including miR-21, and were able to induce T lymphocyte death. Compared to that in HD, miR-21 was overexpressed in both the bone marrow fluid and infiltrating T lymphocytes of AML patients. MiR-21 induces T lymphocyte cell death by upregulating proapoptotic gene expression. It also increases the immunosuppressive profile of T lymphocytes by upregulating the IL13, IL4, IL10, and FoxP3 genes. Conclusions: Our results demonstrate that miR-21 plays a significant role in AML T lymphocyte dysfunction and apoptosis. Targeting miR-21 may be a novel approach to restore the efficacy of the immune response against AML.

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Immune escape and immunotherapy of acute myeloid leukemia

Cited by 218 publications

References 188 publications

Construction of Immune-Related Prognostic Signatures in Acute Myeloid Leukemia

Construction of Immune-Related Prognostic Signatures in Acute Myeloid Leukemia

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

Impact of Bone Marrow miR-21 Expression on Acute Myeloid Leukemia T Lymphocyte Fragility and Dysfunction

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