Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer

Salazar, Ylia; Zheng, Xiang; Brunn, David; Raifer, Hartmann; Picard, Felix S.R.; Zhang, Yajuan; Winter, Hauke; Guenther, Stefan; Weigert, Andreas; Weigmann, Benno; Dumoutier, Laure; Renauld, Jean‐Christophe; Waisman, Ari; Schmall, Anja; Tufman, Amanda; Fink, Ludger; Brüne, Bernhard; Bopp, Tobias; Grimminger, Friedrich; Seeger, Werner; Pullamsetti, Soni Savai; Huber, Magdalena

doi:10.1172/jci124037

Cited by 130 publications

(106 citation statements)

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“…In both cases a significantly reduced migratory behavior was observed compared with the EV control cells. Moreover, based on our previous studies regarding EMT [ 30 , 35 ], we examined the expression of epithelial and mesenchymal markers ( Figure 2 K). Here, we found an increase in epithelial marker expression (CLDN1, Claudin1; CYK18, Cytokeratin18) and a decrease of mesenchymal markers (CDH2, N-cadherin; and CTNNB1, β-Catenin) by FGF14 overexpressing cells compared with the EV control indicating that these cells were in the process of mesenchymal and epithelial transition.…”

Section: Resultsmentioning

confidence: 99%

“…Cg - Prkdc scid Il2rg tm1Wjl / SzJ (NSG) mice were purchased from Charles River Laboratories (Sulzfeld, Germany). A549-EV and A549-FGF14-OE cells (1 × 10 6 ) were randomly injected subcutaneously into the right flank of 6–8-week-old NSG mice as previously described [ 29 , 30 ]. Based on the protocol, the animals were sacrificed after 40 days of tumor growth for further analyses ( n = 7).…”

Section: Methodsmentioning

confidence: 99%

“…In both cases a significantly reduced migratory behavior was observed compared with the EV control cells. Moreover, based on our previous studies regarding EMT [30,35], we examined The measurement of proliferation via BrdU incorporation revealed significantly less proliferation of FGF14 OE cells compared with the EV control ( Figure 2D). To determine the behavior of the FGF14 overexpressing cells, we analyzed the ability of the cells to form colonies (Figure 2E,F).…”

Section: Overexpression Of Fgf14 In Tumor Cells Suppresses Proliferatmentioning

confidence: 99%

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Fibroblast Growth Factor—14 Acts as Tumor Suppressor in Lung Adenocarcinomas

Turkowski

Herzberg

Günther

et al. 2020

Cells

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Investigation of the molecular dynamics in lung cancer is crucial for the development of new treatment strategies. Fibroblast growth factor (FGF) 14 belongs to the FGF family, which might play a crucial role in cancer progression. We analyzed lung adenocarcinoma (LUAC) patients samples and found that FGF14 was downregulated, correlating with reduced survival and oncogenic mutation status. FGF14 overexpression in lung cancer cell lines resulted in decreased proliferation, colony formation, and migration, as well as increased expression of epithelial markers and a decreased expression of mesenchymal markers, indicating a mesenchymal to epithelial transition in vitro. We verified these findings using small interfering RNA against FGF14 and further confirmed the suppressive effect of FGF14 in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ immunodeficient xenograft tumor model. Moreover, FGF14 overexpressing tumor cell RNA sequencing data suggests that genes affected by FGF14 were related to the extracellular matrix, playing a role in proliferation and migration. Notably, newly identified FGF14 target genes, adenosine deaminase RNA specific B1 (ADARB1), collagen and calcium-binding epidermal growth factor domain-containing protein 1 (CCBE1), α1 chain of collagen XI (COL11A1), and mucin 16 (MUC16) expression was negatively correlated with overall survival when FGF14 was downregulated in LUAC. These findings led us to suggest that FGF14 regulates proliferation and migration in LUAC.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…In both cases a significantly reduced migratory behavior was observed compared with the EV control cells. Moreover, based on our previous studies regarding EMT [30,35], we examined The measurement of proliferation via BrdU incorporation revealed significantly less proliferation of FGF14 OE cells compared with the EV control ( Figure 2D). To determine the behavior of the FGF14 overexpressing cells, we analyzed the ability of the cells to form colonies (Figure 2E,F).…”

Section: Overexpression Of Fgf14 In Tumor Cells Suppresses Proliferatmentioning

confidence: 99%

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Fibroblast Growth Factor—14 Acts as Tumor Suppressor in Lung Adenocarcinomas

Turkowski

Herzberg

Günther

et al. 2020

Cells

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“…Furthermore, infiltrating NK cells and TAMs in the tumor microenvironment have strong immunosuppressive activity, which reduces the secretion of IFN-g and induces T cell dysfunction (32,33). Additionally, the subgroup with more Th17 cell infiltration in breast and ovarian cancer is less likely to have lymph node metastasis and more likely to have a better prognosis, which suggests that Th17 cells have anti-tumor effect (34)(35)(36). Therefore, our data elucidated the immunosuppression induced by fewer Th17 cells in the primary tumor microenvironment might result in a lower 10-year survival rate in HTRA3-high patients with GC.…”

Section: Discussionmentioning

confidence: 99%

HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer

Sun

Xing

et al. 2020

Front. Oncol.

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HtrA serine peptidase 3 (HTRA3) participates in multiple signal pathways and plays an important regulatory role in various malignancies; however, its role on prognosis and immune infiltrates in gastric cancer (GC) remains unclear. The study investigated HTRA3 expression in tumor tissues and its association with immune infiltrates, and determined its prognostic roles in GC patients. Patients with GC were collected from the cancer genome atlas (TCGA). We compared the expression of HTRA3 in GC and normal gastric mucosa tissues with Wilcoxon rank sum test. And logistic regression was used to evaluate the relationship between HTRA3 and clinicopathological characters. Gene ontology (GO) term analysis, Gene set enrichment analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) was conducted to explain the enrichmental pathways and functions and quantify the extent of immune cells infiltration for HTRA3. Kaplan-Meier analysis and Cox regression were performed to evaluate the correlation between HTRA3 and survival rates. A nomogram, based on Cox multivariate analysis, was used to predict the impact of HTRA3 on prognosis. High HTRA3 expression was significantly correlated with tumor histological type, histological grade, clinical stage, T stage, and TP53 status (P < 0.05). HTRA3-high GC patients had a lower 10-year progression-free interval [PFI; hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02–2.08; P = 0.038], disease-specific survival (DSS; HR: 1.65; CI: 1.08–2.52; P = 0.021) and overall survival (OS; HR: 1.59; CI: 1.14–2.22; P = 0.006). Multivariate survival analysis showed that HTRA3 was an independent prognostic marker for PFI (HR: 1.456; CI: 1.021–2.078; P = 0.038), DSS (HR: 1.650; CI: 1.079–2.522; P = 0.021) and OS [hazard ratio (HR): 1.590; 95% confidence interval (CI):1.140–2.219; P = 0.006]. The C-indexes and calibration plots of the nomogram based on multivariate analysis indicated an effective predictive performance for GC patients. GSEA showed that High HTRA3 expression may activate NF-κB pathway, YAP1/WWTR1/TAZ pathway, and TGFβ pathway. There was a negative correlation between the HTRA3 expression and the abundances of adaptive immunocytes (T helper cell 17 cells) and a positive correlation with abundances of innate immunocytes (natural killer cells, macrophages etc.). HTRA3 plays a vital role in GC progression and prognosis and could be a moderate biomarker for prediction for survival after gastrectomy.

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“…These cytokines are specific to a suppressive immune response to cancer. Interestingly, miR-21 downregulated the IL7 and class I-restricted T cell-associated molecule (CRTAM) genes, which are known to be associated with the antitumoral response [ 29 ]. To confirm the link between the high expression of miR-21 in AML T lymphocytes and their inability to fight tumor cells, we analyzed the expression of protumoral cytokines using qRT-PCR-designed plates (as described previously).…”

Section: Resultsmentioning

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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Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer

Cited by 130 publications

References 50 publications

Fibroblast Growth Factor—14 Acts as Tumor Suppressor in Lung Adenocarcinomas

Fibroblast Growth Factor—14 Acts as Tumor Suppressor in Lung Adenocarcinomas

HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer

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

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