Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

Abstract

Several studies have demonstrated that NF-kB activation is common in lung cancer; however, the mechanistic links between NF-kB signaling and tumorigenesis remain to be fully elucidated. We investigated the function of NF-kB signaling in epidermal growth factor receptor (EGFR)-mutant lung tumors using a transgenic mouse model with doxycycline (dox)-inducible expression of oncogenic EGFR in the lung epithelium with or without a dominant inhibitor of NF-kB signaling. NF-kB inhibition resulted in a significant reduction in tumor burden in both EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant tumors. However, NF-kB inhibition did not alter epithelial cell survival in vitro or in vivo, and no changes were detected in activation of EGFR downstream signaling pathways. Instead, we observed an influx of inflammatory cells (macrophages and neutrophils) in the lungs of mice with oncogenic EGFR expression that was blocked in the setting of NF-kB inhibition. To investigate whether inflammatory cells play a role in promoting EGFR-mutant lung tumors, we depleted macrophages and neutrophils during tumorigenesis and found that neutrophil depletion had no effect on tumor formation, but macrophage depletion caused a significant reduction in tumor burden. Together, these data suggest that epithelial NFkB signaling supports carcinogenesis in a non-cell autonomous manner in EGFR-mutant tumors through recruitment of pro-tumorigenic macrophages.

Proteomics Analysis for Identification of Potential Cell Signaling Pathways and Protein Targets of Actions of Atractylodin and β-Eudesmol Against Cholangiocarcinoma

“…This pathway is also triggered by ligand-gated receptor binding on the cell surface. The receptors involved include epidermal growth factor receptor (EGFR) (Saxon et al, 2016) toll-like receptor (TLR) (Sun et al, 2017) and tumor necrosis factor receptor (TNFR) (Lee et al, 2017). Activation of these receptors leads to receptor phosphorylation through IKK complex and transcription of the relevant genes.…”

Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

“…Several reports have reported that the tumor microenvironment (TME) [31][32][33][34][35][36], tumor immunogenicity [37][38][39], tumor-specific mutations, copy number variants [40,41] and abundances of specific intestinal bacteria can [42] affect the efficacy of ICIs. Multiple studies have demonstrated that EGFR mutations in NSCLC are more likely to correlate with an immunosuppressive TME [41,[43][44][45][46][47][48], the tumor mutation burden (TMB) [43,49], and expression of PD-L1 [41,[50][51][52][53]. In addition, EGFR-TKIs may modulate the immune response by regulating TME.…”

Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer

“…In mice, expression of a constitutively active form of IKKβ (which activates canonical NF-κB) in airway epithelium results in a >3-fold increase in lung tumor formation after treatment with chemical carcinogens (Zaynagetdinov et al, 2012). In addition, studies using a variety of methods to block NF-κB signaling in lung epithelium have revealed a requirement for NF-κB signaling in lung cancer models driven by oncogenic forms of Kras and EGFR (Bassères et al, 2010; Meylan et al, 2009; Saxon et al, 2016; Stathopoulos et al, 2007; Xia et al, 2012). While some studies have shown short-term lung tumor regression following NF-κB inhibition (Bassères et al, 2014; Xue et al, 2011), pharmacologic NF-κB inhibition has not shown definitive long-term benefit in lung cancer models.…”