TNF-Alpha Pathway Alternation Predicts Survival of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Lin, Anqi; Zhang, Hongman; Meng, Hua; Deng, Ze; Gu, Tianqi; Luo, Peng; Zhang, Jian

doi:10.3389/fimmu.2021.667875

Cited by 11 publications

(8 citation statements)

References 75 publications

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“…Chemokines and cytokines secreted by immune cells in TME are important components of LUAD anti-tumor immunity. 46 The ssGSEA results showed that cytokines and chemokine produced pathways related to immunosuppression, such as IL-10, IL-1β, CCL2 and CXCL2, were significantly down-regulated in the BCR signaling MUT group. 47 These factors recruit tumor-associated macrophages (TAMs), Tregs and Myeloid-derived suppressor cells (MDSCs) into the TME, helping tumor cells escape detection by the immune system and promoting the development and metastasis of tumors.…”

Section: Discussionmentioning

confidence: 94%

B Cell Receptor Signaling Pathway Mutation as Prognosis Predictor of Immune Checkpoint Inhibitors in Lung Adenocarcinoma by Bioinformatic Analysis

Lin¹,

Fang²,

Cheng³

et al. 2022

JIR

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Purpose The advent of immune checkpoint inhibitors (ICIs) is a revolutionary breakthrough. However, without the selection of a specific target population, the response rate of ICI therapy in lung adenocarcinoma (LUAD) is low, so a clinical challenge has arisen in effectively using biomarkers to determine which patients can benefit from ICI therapy. Methods In this study, patients were divided according to whether or not nonsynonymous mutations were present in the BCR signaling pathway, and univariate and multivariate Cox regression models were established based on a LUAD cohort treated with ICIs (Miao-LUAD). Then the relationship between the mutation status of the BCR signaling pathway and the prognosis of immunotherapy was examined. Finally, data from The Cancer Genome Atlas (TCGA) LUAD cohort, the Rizvi-LUAD, the Samstein-LUAD, and the Zhujiang Hospital of Southern Medical University LUAD (Local-LUAD) cohort were combined, and the mutation panorama, immunogenicity, tumor microenvironment (TME) and pathway enrichment analysis between the BCR signaling pathway mutant group (BCR signaling MUT) and the BCR signaling pathway wild group (BCR signaling WT) were comprehensively compared. Results It was found that, compared with the BCR signaling WT, the BCR signaling MUT had a significantly improved progression-free survival (PFS) rate and overall survival (OS) rate, higher immunogenicity (tumor mutational burden, neoantigen load, and DNA damage response signaling mutations), and anti-tumor immune microenvironment. Conclusion These results revealed that the mutation state of the BCR signaling pathway has potential as a biomarker to predict the efficacy of ICIs in LUAD.

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Section: Discussionmentioning

confidence: 94%

B Cell Receptor Signaling Pathway Mutation as Prognosis Predictor of Immune Checkpoint Inhibitors in Lung Adenocarcinoma by Bioinformatic Analysis

Lin¹,

Fang²,

Cheng³

et al. 2022

JIR

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“…Our data provide evidence to support the concept that TNFα signaling reprograms ketone body metabolism, representing a ''wiring'' between metabolism and cell signalling pathways. TNFαmediated chronic inflammation plays an important role in the initiation, metastasis and drug resistance of lung cancer [31][32][33]. Blockade of TNFα signaling can render lung cancer PDXs that express wild-type EGFR sensitive to the treatment of EGFR inhibitors, and improve the therapeutic effect of EGFR inhibitors in lung cancer PDXs with EGFR mutations [32].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation by IKKβ Promotes the Degradation of HMGCL via NEDD4 in Lung Cancer

Zhong¹,

Xiong²,

Yang³

et al. 2023

Int. J. Biol. Sci.

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Inflammation and metabolic reprogramming are hallmarks of cancer. How inflammation regulates cancer metabolism remains poorly understood. In this study, we found that 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), the enzyme that catalyzes the catabolism of leucine and promotes the synthesis of ketone bodies, was downregulated in lung cancer. Downregulation of HMGCL was associated with a larger tumor size and a shorter overall survival time. In a functional study, overexpression of HMGCL increased the content of β-hydroxybutyrate (β-HB) and inhibited the tumorigenicity of lung cancer cells, and deletion of HMGCL promoted de novo tumorigenesis in KP (Kras G12D ;P53 f/f ) mice. Mechanistically, tumor necrosis factor α (TNFα) treatment decreased the HMGCL protein level, and IKKβ interacted with HMGCL and phosphorylated it at Ser258, which destabilized HMGCL. Moreover, NEDD4 was identified as the E3 ligase for HMGCL and promoted its degradation. In addition, mutation of Ser258 to alanine inhibited the ubiquitination of HMGCL by NEDD4 and thus inhibited the anchorage-independent growth of lung cancer cells more efficiently than did wild-type HMGCL. In summary, this study demonstrated a link between TNFα-mediated inflammation and cancer metabolism.

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“…These new tumor antigens can not only enhance the immune response of T cells, but also increase the content of new antigen-specific T cells, thus improving the immune system's ability to identify tumors (32). Studies have shown that the mutation of the DDR pathway will result in the production of higher TMB and neoantigen loads, thus significantly improving the effectiveness of ICI treatment (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Metabolic Signaling Pathway Alternation Predict Prognosis of Immune Checkpoint Inhibitors in Glioblastoma

Liu

Hua

et al. 2022

Front. Immunol.

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IntroductionGlioblastoma(GBM) is a highly malignant primary brain tumor. Even after undergoing surgery and chemotherapy, patients with this affliction still have little to no chance of survival. Current research on immunotherapy treatment for GBM shows that immune-checkpoint inhibitors (ICIs) may be a promising new treatment method. However, at present, the relationship between the fatty acid metabolic process and the prognosis of GBM patients who are receiving immunotherapy is not clear.MethodsFirst, we downloaded a GBM cohort that had been treated with immunotherapy, which included the mutation and prognosis data, and the TCGA-GBM and Jonsson-GBM queues. CIBERSORT and single sample gene set enrichment analysis(ssGSEA) were used to evaluate immune cell scores. Gene set enrichment analysis (GSEA) was used to evaluate the patient’s accessment score. The pRRophetic algorithm was used to evaluate the drug sensitivity of each patient. Univariable and multivariate cox regression analyses, as well as the Kaplan-Meier (KM) method, were used to evaluate the relationship between the fatty acid metabolic process and the prognosis of GBM patients.ResultsThe univariate and multivariate cox regression models showed that the fatty acid metabolic process mutant-type (MT) can be used as an independent predictor of the efficacy of immunotherapy for GBM patients. In addition, fatty acid metabolic process MT is related with significantly longer overall survival (OS) time than the wild-type(WT) variant. However, the mutation status of the fatty acid metabolic process has nothing to do with the prognosis of GBM patients who are receiving conventional treatment. Our analysis showed that fatty acid metabolic process MT correlated with significantly increased natural killer T (NKT) cells and significantly decreased CD8+T cells. At the same time, GSEA analysis revealed that fatty acid metabolic process MT was associated with significantly increased immune activation pathways and an enriched fraction of cytokine secretion compared with WT.ConclusionsWe found that fatty acid metabolic process MT may be used as an independent predictor of the efficacy of ICI treatment in GBM patients. Use of the fatty acid metabolic process MT will result in higher immunogenicity rates, a significant increase in the proportion of activated immune cells, and improvement of the immune microenvironment.

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TNF-Alpha Pathway Alternation Predicts Survival of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Cited by 11 publications

References 75 publications

B Cell Receptor Signaling Pathway Mutation as Prognosis Predictor of Immune Checkpoint Inhibitors in Lung Adenocarcinoma by Bioinformatic Analysis

B Cell Receptor Signaling Pathway Mutation as Prognosis Predictor of Immune Checkpoint Inhibitors in Lung Adenocarcinoma by Bioinformatic Analysis

Phosphorylation by IKKβ Promotes the Degradation of HMGCL via NEDD4 in Lung Cancer

Fatty Acid Metabolic Signaling Pathway Alternation Predict Prognosis of Immune Checkpoint Inhibitors in Glioblastoma

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