The Role of Tumor Necrosis Factor in Manipulating the Immunological Response of Tumor Microenvironment

Laha, Dipranjan; Grant, Robert; Mishra, Prachi; Nilubol, Naris

doi:10.3389/fimmu.2021.656908

Cited by 108 publications

(65 citation statements)

References 130 publications

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“…3 B). However, RNA-seq analysis of NFAT1 indicated that the expression of TNF, an activator of TNF signaling [ 24 ], was downregulated after NFAT1 silencing (Fig. 2 ).…”

Section: Resultsmentioning

confidence: 99%

A novel FBW7/NFAT1 axis regulates cancer immunity in sunitinib-resistant renal cancer by inducing PD-L1 expression

Ren

Wang

et al. 2022

J Exp Clin Cancer Res

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Background Tyrosine kinase inhibitors (TKIs) alone and in combination with immune checkpoint inhibitors (ICIs) have been shown to be beneficial for the survival of metastatic renal cell carcinoma (mRCC) patients, but resistance to targeted therapy and ICIs is common in the clinic. Understanding the underlying mechanism is critical for further prolonging the survival of renal cancer patients. Nuclear factor of activated T cell 1 (NFAT1) is expressed in immune and nonimmune cells, and the dysregulation of NFAT1 contributes to the progression of various type of malignant tumors. However, the specific role of NFAT1 in RCC is elusive. As a regulator of the immune response, we would like to systemically study the role of NFAT1 in RCC. Methods TCGA-KIRC dataset analysis, Western blot analysis and RT-qPCR analysis was used to determine the clinic-pathological characteristic of NFAT1 in RCC. CCK-8 assays, colony formation assays and xenograft assays were performed to examine the biological role of NFAT1 in renal cancer cells. RNA-seq analysis was used to examine the pathways changed after NFAT1 silencing. ChIP-qPCR, coimmunoprecipitation analysis, Western blot analysis and RT-qPCR analysis were applied to explore the mechanism by NAFT1 was regulated in the renal cancer cells. Results In our study, we found that NFAT1 was abnormally overexpressed in RCC and that NFAT1 overexpression was associated with an unfavorable prognosis. Then, we showed that NFAT1 enhanced tumor growth and regulated the immune response by increasing PD-L1 expression in RCC. In addition, we demonstrated that NFAT1 was stabilized in sunitinib-resistant RCC via hyperactivation of the PI3K/AKT/GSK-3β signaling pathway. Furthermore, our study indicated that downregulation of the expression of FBW7, which promotes NFAT1 degradation, was induced by FOXA1 and SETD2 in sunitinib-resistant RCC. Finally, FBW7 was found to contribute to modulating the immune response in RCC. Conclusions Our data reveal a novel role for the FBW7/NFAT1 axis in the RCC response to TKIs and ICIs. NFAT1 and its associated signaling pathway might be therapeutic targets for RCC treatment, especially when combined with ICIs and/or TKIs.

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“…3 B). However, RNA-seq analysis of NFAT1 indicated that the expression of TNF, an activator of TNF signaling [ 24 ], was downregulated after NFAT1 silencing (Fig. 2 ).…”

Section: Resultsmentioning

confidence: 99%

A novel FBW7/NFAT1 axis regulates cancer immunity in sunitinib-resistant renal cancer by inducing PD-L1 expression

Ren

Wang

et al. 2022

J Exp Clin Cancer Res

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“…TNF-α plays a critical role in tumor signaling pathways and immune-cell manipulation within the TME.TNF-α induces diverse effects that are both oncogenic and tumor-suppressive [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

Effect of Poly(methacrylic acid) on the Cytokine Level in an In Vivo Tumor Model

et al. 2022

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Cancer is a leading cause of mortality globally. Despite remarkable improvements in cancer-treatment approaches, disease recurrence and progression remain major obstacles to therapy. While chemotherapy is still a first-line treatment for a variety of cancers, the focus has shifted to the development and application of new approaches to therapy. Nevertheless, the relationship between immune response, neoplastic diseases and treatment efficiency is not fully understood. Therefore, the aim of the study was to investigate the immunopharmacological effects of methacrylic acid homopolymer in an in vivo tumor model. Materials and methods: Monomeric methacrylic acid was used to synthesize polymers. Methacrylic acid was polymerized in dioxane in the presence of 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid. To study the molecular weight characteristics of PMAA by GPC, carboxyl groups were preliminarily methylated with diazomethane. An experimental cancer model was obtained by grafting RMK1 breast cancer cells. The serum levels of IL-6, IL-10, IL-17, transforming growth factor β1 (TGF-β1), and tumor necrosis factor α (TNF-α) were measured by ELISA. Results: The effect of PMAA on the serum concentrations of several cytokines was studied upon its single administration to laboratory animals in early neoplastic process. The IL-6, IL-17 and TGF-β1 concentrations were found to change significantly and reach the level observed in intact rats. The IL-10 concentration tended to normalize. Conclusion: The positive results obtained are the basis for further studies on the effect of methacrylic-acid polymers with different molecular-weight characteristics on the neoplastic process.

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“…Other molecules directly connected to the central node were several pro-inflammatory molecules IL1B, IKK, IKB, and ERBB2. Oncogenic TGF-β signaling has been linked to PCa; nevertheless, a signature of TGF-β-regulated ECM genes has been identified in many CAFs and associated with poor prognosis [ 17 , 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer

Mantovani

Caraglia

Jung

et al. 2022

Cancers

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Background: Stromal components surrounding epithelial cancer cells seem to play a pivotal role during epithelial-to-mesenchymal transition (EMT), tumor invasion, and metastases. To identify the molecular mechanisms underlying tumor–stroma interactions may yield novel therapeutic targets for prostate cancer. Methods: Gene expression profile of prostate-cancer associated fibroblast (PCAF) and prostate non-cancer associated fibroblast (PNAF) cells isolated from radical prostatectomy was performed by Illumina, analyzed, and further processed by Ingenuity®: IPA® software. qRT-PCR was performed on an independent set of 17 PCAF, 12 PNAF, and 12 fibroblast cell lines derived from patients with benign prostatic hyperplasia (BPHF). Results: Using microarray analysis, we found six upregulated genes and two downregulated genes in PCAFs compared to PNAFs. To validate microarray results, we performed qRT-PCR for the most significantly regulated genes involved in the modulation of proliferation and androgen resistance on an independent set of PNAF, PCAF, and BHPF samples. We confirmed the increased expression of SCARB1, MAPK3K1, and TGF-β as well as the decreased expression of S100A10 in PCAFs compared to PNAFs and BPHFs. Conclusions: These results provide strong evidence that the observed changes in the gene expression profile of PCAFs can contribute to functional alteration of adjacent prostate cancer cells.

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The Role of Tumor Necrosis Factor in Manipulating the Immunological Response of Tumor Microenvironment

Cited by 108 publications

References 130 publications

A novel FBW7/NFAT1 axis regulates cancer immunity in sunitinib-resistant renal cancer by inducing PD-L1 expression

A novel FBW7/NFAT1 axis regulates cancer immunity in sunitinib-resistant renal cancer by inducing PD-L1 expression

Effect of Poly(methacrylic acid) on the Cytokine Level in an In Vivo Tumor Model

Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer

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