TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients

Rakova, Jana; Truxová, Iva; Holicek, Peter; Šálek, Cyril; Hensler, Michal; Kašíková, Lenka; Pasulka, Josef; Holubová, Monika; Kovář, Marek; Lysák, Daniel; Kline, Justin; Ráčil, Zdeněk; Galluzzi, Lorenzo; Špíšek, Radek; Fučíková, Jitka

doi:10.1080/2162402x.2021.1889822

Cited by 37 publications

(18 citation statements)

References 50 publications

(71 reference statements)

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“…HAVCR2 recruits immune cells and is positively correlated with the expression levels of CCL18, CXCL13, and CCL7, which can be used for predicting the prognosis of GBM patients [ 47 ]. Moreover, HAVCR2 levels are correlated with enhanced NK cell cytotoxicity and improved clinical outcomes in AML patients [ 48 ]. In addition, PDCD1LG2 overexpression is associated with poor prognosis in hepatocellular carcinoma patients [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Potential Immune Checkpoint Inhibitor Targets in Gliomas via Bioinformatic Analyses

Ding¹,

Li²,

et al. 2022

BioMed Research International

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Background. Glioma is a common tumor originating from the glial cells of the brain. Immune checkpoint inhibitors can potentially be used to treat gliomas, although no drug is currently approved. Methods. The expression levels of the immune checkpoint genes in glioma and normal tissues, and their correlation with the IDH mutation status and complete 1p/19q codeletion, were analyzed using The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Survival analyses were conducted using the CGGA database. Protein-protein interaction and functional enrichment analyses were performed via the STRING database using GO, KEGG, and Reactome pathways. The correlation between the immune checkpoints and the immune cell infiltration was determined using the TISIDB and TIMER databases. Results. HAVCR2 was overexpressed in the gliomas compared to normal brain tissues, as well as in the high-grade glioma patients and significantly downregulated in IDH mutant or 1p/19q codeletion patients. Overexpression of HAVCR2 was associated with poor survival in tumor grades II, III, and IV and was the most correlated with immune infiltration of B and T cells. Conclusion. HAVCR2 can be a potential therapeutic target for cancer immunotherapy for glioma patients.

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Section: Discussionmentioning

confidence: 99%

Identification of Potential Immune Checkpoint Inhibitor Targets in Gliomas via Bioinformatic Analyses

Ding¹,

Li²,

et al. 2022

BioMed Research International

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“…TIM-3 positivity was associated with T-cell exhaustion, but also with increased cytotoxic capacity of NK cells [40,41]. In AML, higher numbers of TIM-3+ NK cells at diagnosis were recently reported to predict better outcome [42]. TIM-3 is also known to be present on the surface of AML blasts [43], but its role in leukemogenesis or in leukemia maintenance is still not clear.…”

Section: Discussionmentioning

confidence: 99%

Associations between recurrent mutations and blast immunophenotype in acute myeloid leukemia

Kuželová

Brodská

Marková

et al. 2021

Preprint

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The immune system undoubtly plays an important role in final elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. However, the anti-leukemia immune response can be inhibited by a variety of mechanisms enabling immune escape and eventual disease relapse. We analyzed selected markers of immune escape on AML cells at diagnosis (N = 53) and used them for hierarchical clustering analysis, which yielded distinct clusters with different incidence of mutations in nucleophosmin 1 (NPM1) and in the methyltransferase DNMT3A. More detailed analysis showed that in the absence of DNMT3A mutation, NPM1 mutation is associated with decreased HLA expression and also with low levels of other markers (CLIP, PD-L1, TIM-3). On the other hand, samples with concomitant DNMT3A mutation had high CLIP surface amount suggesting reduced antigen presentation. Higher CLIP exposition was also found in patients with internal tandem duplications in FLT3 (FLT3-ITD). TIM-3 transcript correlated not only with TIM-3 protein surface amount, but also with CLIP and PD-L1, suggesting acquisition of a complex immunoresistant phenotype. Our results indicate that AML genotype is to some extent related to the blast immunophenotype, and the established predictive values of particular mutations might also reflect an inherent cell resistance to the immune system.

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“…observed NK cell activity in AML patients. This group revealed that TIM-3 upregulation on these cells was associated with increased activity of NK cells and resulted in better clinical outcome for AML patients ( 58 ) ( Table 1 ). As noted, exceptional studies have been performed on TIM-3 in AML, yet so many aspects are still intact or not completely examined.…”

Section: Alterations In Tim-3 Expression In Patients With Leukemiamentioning

confidence: 98%

TIM-3 in Leukemia; Immune Response and Beyond

et al. 2021

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T cell immunoglobulin and mucin domain 3 (TIM-3) expression on malignant cells has been reported in some leukemias. In myelodysplastic syndrome (MDS), increased TIM-3 expression on TH1 cells, regulatory T cells, CD8+ T cells, and hematopoietic stem cells (HSCs), which play a role in the proliferation of blasts and induction of immune escape, has been reported. In AML, several studies have reported overexpression of TIM-3 on leukemia stem cells (LSCs) but not on healthy HSCs. Overexpression of TIM-3 on exhausted CD4+ and CD8+ T cells and leukemic cells in CML, ALL, and CLL patients could be a prognostic risk factor for poor therapeutic response and relapse in patients. Currently, several TIM-3 inhibitors are used in clinical trials for leukemias, and some have shown encouraging response rates for MDS and AML treatment. For AML immunotherapy, blockade TIM-3 may have dual effects: directly inhibiting AML cell proliferation and restoring T cell function. However, blockade of PD-1 and TIM-3 fails to restore the function of exhausted CD8+ T cells in the early clinical stages of CLL, indicating that the effects of TIM-3 blockade may be different in AML and other leukemias. Thus, further studies are required to evaluate the efficacy of TIM-3 inhibitors in different types and stages of leukemia. In this review, we summarize the biological functions of TIM-3 and its contribution as it relates to leukemias. We also discuss the effects of TIM-3 blockade in hematological malignancies and clinical trials of TIM-3 for leukemia therapy.

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TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients

Cited by 37 publications

References 50 publications

Identification of Potential Immune Checkpoint Inhibitor Targets in Gliomas via Bioinformatic Analyses

Identification of Potential Immune Checkpoint Inhibitor Targets in Gliomas via Bioinformatic Analyses

Associations between recurrent mutations and blast immunophenotype in acute myeloid leukemia

TIM-3 in Leukemia; Immune Response and Beyond

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