Controlling the Immune Suppressor: Transcription Factors and MicroRNAs Regulating CD73/NT5E

Kordaß, Theresa; Osen, Wolfram; Eichmüller, Stefan B.

doi:10.3389/fimmu.2018.00813

Cited by 82 publications

(69 citation statements)

References 95 publications

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“…The immunosuppressive nature of the membrane bound ectonucleotidase CD73 converting extracellular AMP to adenosine has been extensively reviewed 35,36 . Inhibition of CD73 was shown to suppress tumour growth in syngeneic mouse models [37][38][39] , and in fact, a first phase I/IB clinical trial investigating the preliminary activity of CD73 blocking antibody in combination with antibodies against anti PD-1 and/or adenosine A2A receptor in patients with advanced malignancies including PDA has been initiated in July 2018 40 .…”

Section: Discussionmentioning

confidence: 99%

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Schröter

Hartmann

Osen

et al. 2020

Sci Rep

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Pancreatic ductal adenocarcinoma (PDA) is highlighted by resistance to radiotherapy with the possible exception of hypofractionated irradiation. As single photon doses were reported to increase immunogenicity, we investigated dose-dependent irradiation effects on clonogenic survival, expression of immunologically relevant cell surface molecules and susceptibility to cytotoxic T cell (CTL) mediated killing using a murine PDA cell line. Clonogenicity decreased in a dose-responsive manner showing enhanced radioresistance at single photon doses below 5 Gy. Cell cycle analysis revealed a predominant G2/M arrest, being most pronounced 12 h after irradiation. Polyploidy increased in a dose-and timedependent manner reaching a maximum frequency 60 h following irradiation with 10 Gy. Irradiation increased surface expression of MHC class I molecules and of immunological checkpoint molecules PDL-1 and CD73, especially at doses ≥ 5 Gy, but not of MHC class II molecules and CXCR4 receptors. Cytotoxicity assays revealed increased CTL lysis of PDA cells at doses ≥ 5 Gy. For the PDA cell line investigated, our data show for the first time that single photon doses ≥ 5 Gy effectively inhibit colony formation and induce a G2/M cell cycle arrest. Furthermore, expression levels of immunomodulatory cell surface molecules became altered possibly enhancing the susceptibility of tumour cells to CTL lysis.Despite application of continuously evolving treatment techniques and their individual escalation, prognosis for patients with PDA has remained dismal 1 . The role of radiotherapy in the multimodal treatment approach of PDA has been controversially discussed. In fact, due to its intrinsic properties this tumour entity is generally considered as highly radioresistant and non-immunogenic 2,3 . Recently, several trials have identified hypofractionated photon dose regimens to be associated with increased local control and thus potentially also with survival rates 4-7 . In conventional radiation biology, the use of increased ablative single photon doses commonly overcomes tumour-intrinsic radioresistance by inhibiting repopulation of tumour cells and repair of DNA damage that occur during normofractionated radiotherapy.Several preclinical and clinical trials found increased single photon doses capable of eliciting immunological effects turning irradiated tumours and their stroma into pharmacologically targetable compartments 8 . Regarding PDA, only few preclinical studies have revealed immune stimulatory radiogenic effects so far; the same holds true for studies investigating the clinical benefit of radiotherapy approaches combined with immune checkpoint blockade 9-11 . Currently, there is no consensus about the appropriate photon doses that should be applied in order to induce immunomodulatory alterations in addition to merely anti-proliferative effects. While most of

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Section: Discussionmentioning

confidence: 99%

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Schröter

Hartmann

Osen

et al. 2020

Sci Rep

Self Cite

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“…Interestingly, shIF1 cells reveal significant increased expression of the CXC chemokine receptor 4 (CXCR4), which is involved in the inhibition of the activation and proliferation of NK cells by tumor cells [48,49] (Figure 7E). Moreover, shIF1 cells significantly increased the expression of the transcription factor SMAD3 and of the ecto-5'nucleotidase CD73/NT5E, which is under the control of SMAD3, an enzyme that generates adenosine in the tumor microenvironment leading to the suppression of multiple immune subsets including NK cells [50,51] ( Figure 7E). In addition, the mRNA of LDHA (two fold, false discovery rate (FDR) < 0.007) was also significantly increased in shIF1 cells, suggesting that they produce more lactate which might be released to the tumor microenvironment acting also as an immune metabolite that hampers immune surveillance and activation of NK cells [52] ( Figure 7E).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells

González-Llorente

Santacatterina

Bocanegra

et al. 2019

Cancers

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Increasing evidences show that the ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of the ATP synthase, is overexpressed in a large number of carcinomas contributing to metabolic reprogramming and cancer progression. Herein, we show that in contrast to the findings in other carcinomas, the overexpression of IF1 in a cohort of colorectal carcinomas (CRC) predicts less chances of disease recurrence, IF1 being an independent predictor of survival. Bioinformatic and gene expression analyses of the transcriptome of colon cancer cells with differential expression of IF1 indicate that cells overexpressing IF1 display a less aggressive behavior than IF1 silenced (shIF1) cells. Proteomic and functional in vitro migration and invasion assays confirmed the higher tumorigenic potential of shIF1 cells. Moreover, shIF1 cells have increased in vivo metastatic potential. The higher metastatic potential of shIF1 cells relies on increased cFLIP-mediated resistance to undergo anoikis after cell detachment. Furthermore, tumor spheroids of shIF1 cells have an increased ability to escape from immune surveillance by NK cells. Altogether, the results reveal that the overexpression of IF1 acts as a tumor suppressor in CRC with an important anti-metastatic role, thus supporting IF1 as a potential therapeutic target in CRC.

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“…NT5E is also known as CD73 . CD73 is a membrane protein that cleaves extracellular nucleotides to nucleosides (Kordass, Osen, & Eichmuller, ). It is also considered as one of the surface markers for mesenchymal stem cells (Dominici et al, ).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of Jagged1‐treated human periodontal ligament cells

et al. 2019

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Objective: Jagged1 regulates several biological functions in human periodontal ligament cells (hPDLs). The present study aimed to evaluate mRNA expression profiling of Jagged1-treated hPDLs using microarray technique. Methods:Notch ligands, Jagged1, were indirectly immobilized on tissue culture surface. Subsequently, hPDLs were seeded on Jagged1 immobilized surface and maintained in growth medium for 48 hr. Total RNA was collected and processed. Gene expression profiling was examined using microarray technique. Real-time polymerase chain reaction and immunofluorescence staining were employed to determine mRNA and protein expression levels, respectively. Cell proliferation and colony-forming unit assay were performed. Cell cycle was evaluated using propidium iodide staining and flow cytometry analysis. Results:The isolated cells demonstrated fibroblast-like morphology and exhibited the co-expression of CD44, CD90, and CD105 surface markers. After stimulated with Jagged1, the total of 411 genes was differentially expressed, consisting both coding and non-coding genes. For coding genes, 165 and 160 coding genes were upregulated and downregulated, respectively. Pathway analysis revealed that the upregulated genes were mainly involved in cellular interactions, signal transduction, and collagen formation and degradation while the downregulated genes were in the events and phases in cell cycle. Jagged1 significantly decreased cell proliferation, reduced colony-forming unit ability, and induced G0/G1 cell cycle arrest in hPDLs.

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Controlling the Immune Suppressor: Transcription Factors and MicroRNAs Regulating CD73/NT5E

Cited by 82 publications

References 95 publications

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells

Gene expression profiling of Jagged1‐treated human periodontal ligament cells

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