Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment

Ke Gong, Gao Guo, Nicole Beckley, Yue Zhang, Xiaoyao Yang, Mishu Sharma, Amyn A Habib, Ke Gong, Gao Guo, Nicole Beckley, Yue Zhang, Xiaoyao Yang, Mishu Sharma, Amyn A Habib

Abstract

Tumor necrosis factor (TNF) and its receptors are widely expressed in non-small cell lung cancer (NSCLC). TNF has an established role in inflammation and also plays a key role in inflammation-induced cancer. TNF can induce cell death in cancer cells and has been used as a treatment in certain types of cancer. However, TNF is likely to play an oncogenic role in multiple types of cancer, including NSCLC. TNF is a key activator of the transcription factor NF-κB. NF-κB, in turn, is a key effector of TNF in inflammation-induced cancer. Data from The Cancer Genome Atlas database suggest that TNF could be a biomarker in NSCLC and indicate a complex role for TNF and its receptors in NSCLC. Recent studies have reported that TNF is rapidly upregulated in NSCLC in response to targeted treatment with epidermal growth factor receptor (EGFR) inhibition, and this upregulation leads to NF-κB activation. The TNF upregulation and consequent NF-κB activation play a key role in mediating both primary and secondary resistance to EGFR inhibition in NSCLC, and a combined inhibition of EGFR and TNF can overcome therapeutic resistance in experimental models. TNF may mediate the toxic side effects of immunotherapy and may also modulate resistance to immune checkpoint inhibitors. Drugs inhibiting TNF are widely used for the treatment of various inflammatory and rheumatologic diseases and could be quite useful in combination with targeted therapy of NSCLC and other cancers.

Trial registration: ClinicalTrials.gov NCT00410059.

Keywords: EGFR inhibition; Immunotherapy; NSCLC; TCGA; TNF; Therapeutic resistance.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
TNF affects TCGA-NSCLC patient survival. (A−C) The Cancer Genome Atlas Lung Squamous Cell Carcinoma (TCGA-LUSC) patients with RNAseq and survival data were divided into high-50% and low-50% groups by TNF, TNFR1, and TNFR2 mRNA levels and the effect on overall survival was examined. Kaplan–Meier (KM) survival curves were drawn and compared by log-rank test and Gehan's test. (D−F) 500 primary TCGA-Lung Adenocarcinoma (TCGA-LUAD) patients’ RNAseq and survival data was analyzed. (G−I). Among the 500 primary TCGA-LUAD patients, there are 41 patients harboring EGFR-activating mutation (with L858R or exon 19 deletion, but without T790M mutation). Roles of TNF/TNFR1/TNFR2 on these patients’ survival data was examined. P <0.05 of log-rank was considered statistically significant. Analysis was performed by GraphPad 9. TCGA, The Cancer Genome Atlas; TNF, tumor necrosis factor; TNFR1, TNF receptor 1; TNFR2, TNF receptor 2.
Figure 2
Figure 2
Higher TNF superfamily ligands and receptors determine worse prognosis of NSCLC patients treated with EGFR inhibition. (A) A summary table of survival analysis on TNF superfamily ligands and receptors in the BATTLE trial data (ClinicalTrials.gov NCT00410059 for erlotinib). The higher HR (Hazard Ratio) >1 means the gene would likely promote tumor growth and shorten the progression-free survival (PFS). BATTLE data were provided by the BATTLE group at MD Anderson Cancer Center . (B−D) KM survival curves were drawn on 3 TNF superfamily ligands (TNFSFs) with top 5 HR, the other 2 ligands TNF and LTB was reported in our previous study . (E) The first principle component (PC1) score of current known TNFSFs and TNF superfamily receptors (TNFRSFs) as listed in the Figure 2A for each patient in NCT00410059 was calculated. Patients with higher or lower PC1 scores were compared by KM survival analysis. (F) All gene survival analysis was performed on NCT00410059. All genes were ranked by HR to distinguish oncogenes and tumor suppressors. The enrichment plot by Gene Set Enrichment Analysis (GSEA) shows TNFSF & TNFRSF signature (genes in the Figure 2A) was significantly enriched in oncogenes, genes with higher HR that bring in shorter PFS under erlotinib treatment. (G) KM survival curves of IκBα. P <0.05 of log-rank was considered statistically significant. Analysis was performed by GraphPad 9, and GSEA: www.gsea-msigdb.org. BATTLE, Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination; NSCLC, non-small cell lung cancer; TNF, tumor necrosis factor; TNFSFs, TNF superfamily ligands.
Figure 3
Figure 3
Schematic diagram of TNF signaling and the effect of EGFR and TNF inhibition in NSCLC. Representative TNF superfamily ligands and receptors predicting worse prognosis in the BATTLE trial with statistically significance were labelled in red. BATTLE, Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination; NSCLC, non-small cell lung cancer; TNF, tumor necrosis factor. (Color version of figure is available online.)

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