scholarly journals Interferon β and Anti-PD-1/PD-L1 Checkpoint Blockade Cooperate in NK Cell-Mediated Killing of Nasopharyngeal Carcinoma Cells

2019 ◽  
Vol 12 (9) ◽  
pp. 1237-1256 ◽  
Author(s):  
Anna Makowska ◽  
Till Braunschweig ◽  
Bernd Denecke ◽  
Lian Shen ◽  
Valentin Baloche ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Nk Cell ◽  
Carcinoma Cells ◽  
Checkpoint Blockade ◽  
Interferon Β

scholarly journals Radiotherapy Combined with PD-1 Inhibition Increases NK Cell Cytotoxicity towards Nasopharyngeal Carcinoma Cells

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2458
Author(s):  
Anna Makowska ◽  
Nora Lelabi ◽  
Christina Nothbaum ◽  
Lian Shen ◽  
Pierre Busson ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Nk Cells ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Carcinoma Cells ◽  
Checkpoint Blockade ◽  
Therapeutic Modality ◽  
Release Assay ◽  
Nk Cell Cytotoxicity ◽  
Calcein Release

Background: Nasopharyngeal carcinoma (NPC) in endemic regions and younger patients is characterized by a prominent lymphomononuclear infiltration. Radiation is the principal therapeutic modality for patients with NPC. Recent data suggest that the efficacy of radiotherapy in various cancers can be augmented when combined with immune checkpoint blockade. Here, we investigate the effect of radiotherapy on the killing of NPC cells by Natural Killer (NK) cells. Methods: NPC cell lines and a patient-derived xenograft were exposed to NK cells in the context of radiotherapy. Cytotoxicity was measured using the calcein-release assay. The contribution of the PD-L1/PD-1 checkpoint and signaling pathways to killing were analyzed using specific inhibitors. Results: Radiotherapy sensitized NPC cells to NK cell killing and upregulated expression of PD-1 ligand (PD-L1) in NPC cells and PD-1 receptor (PD-1) in NK cells. Blocking of the PD-L1/PD-1 checkpoint further increased the killing of NPC cells by NK cells in the context of radiotherapy. Conclusion: Radiation boosts the killing of NPC cells by NK cells. Killing can be further augmented by blockade of the PD-L1/PD-1 checkpoint. The combination of radiotherapy with PD-L1/PD-1 checkpoint blockade could therefore increase the efficacy of radiotherapy in NPC tumors.

Overexpression of p62 Induces Autophagy and Promotes Proliferation, Migration and Invasion of Nasopharyngeal Carcinoma Cells through Promoting ERK Signaling Pathway

2020 ◽  
Vol 20 (8) ◽  
pp. 624-637 ◽  
Author(s):  
Qiong Wu ◽  
Manlin Xiang ◽  
Kun Wang ◽  
Zhen Chen ◽  
Lu Long ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Clinical Analysis ◽  
Carcinoma Cells ◽  
Immunofluorescent Staining ◽  
Clinicopathological Parameters ◽  
Migration And Invasion ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Potential Biomarker

Background: Increasing evidence has shown that p62 plays an important role in tumorigenesis. However, relatively little is known about the association between p62 and tumor invasion and metastasis; in addition, its role in NPC (nasopharyngeal carcinoma, NPC) has been rarely investigated. Objective: To investigate the effect of p62 on tumorigenesis and metastasis in nasopharyngeal carcinoma. Methods: Western blotting, immunofluorescent staining and immunohistochemistry were used to evaluate p62 protein expression. Subsequently, cell viability, colony formation, migration, invasion and autophagy assays were performed. anti-p62 autoantibodies in sera were detected by ELISA. These data were correlated with clinicopathological parameters. Results: We confirmed that p62 was significantly up-regulated in NPC tissues. Furthermore, high expression of p62 was observed in NPC cell lines, and especially in the highly metastatic 5-8F cells. In vitro, down-regulation of p62 inhibited proliferation, clone forming ability, autophagy, migration, and invasion in 5-8F cells, whereas p62 overexpression resulted in the opposite effects in 6-10B cells. Moreover, we confirmed that p62 promotes NPC cell proliferation, migration, and invasion by activating ERK (extracellular signal-regulated kinase, ERK). Clinical analysis indicated that high p62 expression correlates with lymph node and distant metastasis (P<0.05). Serum anti-p62 autoantibodies were increased in NPC patients and levels were associated with metastasis. Conclusion : Our data establish p62 targeting ERK as potential determinant in the NPC, which supplies a new pathway to treat NPC. Furthermore, p62 is a potential biomarker which might be closely related to the tumorigenesis and metastasis in NPC.

scholarly journals IMMU-09. CONCURRENT DEXAMETHASONE LIMITS THE CLINICAL BENEFIT OF IMMUNE CHECKPOINT BLOCKADE IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii106-ii106
Author(s):  
Bryan Iorgulescu ◽  
Prafulla Gokhale ◽  
Maria Speranza ◽  
Benjamin Eschle ◽  
Michael Poitras ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Innate Immune Responses ◽  
Dose Dependent Fashion ◽  
Dexamethasone Therapy ◽  
Clinical Correlate ◽  
Dose Dependent

Abstract BACKGROUND Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy. METHODS We evaluated the dose-dependent effects of dexamethasone when administered with anti-PD-1 and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 or CT-2A glioblastoma tumors, including analyses of intracranial tumors, draining lymph nodes, and spleen. Clinically, the effect of dexamethasone on survival was additionally evaluated in 181 consecutive IDH-wildtype glioblastoma patients treated with anti-PD-(L)1, with adjustment for relevant prognostic factors. RESULTS Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy decreased survival in a dose-dependent fashion and decreased survival following anti-PD-1 plus radiotherapy in both GL261 and immunoresistant CT-2A models. Dexamethasone quantitatively decreased T lymphocytes by reducing the proliferation while increasing apoptosis. Dexamethasone also decreased lymphocyte functional capacity. Myeloid and NK cell populations were also generally reduced. Thus, dexamethasone negatively affects both the adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed worse survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone use – regardless of dose – was the strongest predictor of poor survival (reference no dexamethasone; &lt; 2mg HR 2.28, 95%CI=1.41–3.68, p=0.001; ≥2mg HR 1.97, 95%CI=1.27–3.07, p=0.003). CONCLUSIONS Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for glioblastoma patients. Our preclinical analyses also suggest that dexamethasone’s detrimental effects are dose-dependent, suggesting that the lowest possible dose should be used for patients when dexamethasone use is unavoidable. Careful evaluation of dexamethasone use is warranted for neuro-oncology patients undergoing immunotherapy clinical trials.

Chk1 inhibitor Gö6976 enhances the sensitivity of nasopharyngeal carcinoma cells to radiotherapy and chemotherapy in vitro and in vivo

2010 ◽  
Vol 297 (2) ◽  
pp. 190-197 ◽  
Author(s):  
Zizhen Feng ◽  
Shuangbing Xu ◽  
Mengzhong Liu ◽  
Yi-Xin Zeng ◽  
Tiebang Kang
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Carcinoma Cells ◽  
Chk1 Inhibitor

scholarly journals Long non-coding (lnc)RNA profiling and the role of a key regulator lnc-PNRC2-1 in the transforming growth factor-β1-induced epithelial–mesenchymal transition of CNE1 nasopharyngeal carcinoma cells

2021 ◽  
Vol 49 (3) ◽  
pp. 030006052199651
Author(s):  
Jie Yang ◽  
Enzi Feng ◽  
Yanxin Ren ◽  
Shun Qiu ◽  
Liufang Zhao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Nasopharyngeal Carcinoma ◽  
Rna Sequencing ◽  
Western Blotting ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cells ◽  
Mesenchymal Transition ◽  
Emt Markers ◽  
Tgf Β1

Objectives To identify key long non-coding (lnc)RNAs responsible for the epithelial–mesenchymal transition (EMT) of CNE1 nasopharyngeal carcinoma cells and to investigate possible regulatory mechanisms in EMT. Methods CNE1 cells were divided into transforming growth factor (TGF)-β1-induced EMT and control groups. The mRNA and protein expression of EMT markers was determined by real-time quantitative PCR and western blotting. Differentially expressed genes (DEGs) between the two groups were identified by RNA sequencing analysis, and DEG functions were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. EMT marker expression was re-evaluated by western blotting after knockdown of a selected lncRNA. Results TGF-β1-induced EMT was characterized by decreased E-cadherin and increased vimentin, N-cadherin, and Twist expression at both mRNA and protein levels. Sixty lncRNA genes were clustered in a heatmap, and mRNA expression of 14 dysregulated lncRNAs was consistent with RNA sequencing. Knockdown of lnc-PNRC2-1 increased expression of its antisense gene MYOM3 and reduced expression of EMT markers, resembling treatment with the TGF-β1 receptor inhibitor LY2109761. Conclusion Various lncRNAs participated indirectly in the TGF-β1-induced EMT of CNE1 cells. Lnc-PNRC2-1 may be a key regulator of this and is a potential target to alleviate CNE1 cell EMT.

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