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Oncogenic epidermal growth factor receptor signal-induced histone deacetylation suppresses chemokine gene expression in human lung adenocarcinoma.

ABSTRACT: Epidermal growth factor receptor (EGFR)-mutated (mt) lung adenocarcinoma (LA) is refractory to immune checkpoint inhibitors (ICIs). However, the mechanisms have not been fully elucidated. CD8⁺ T cell infiltration was significantly lower in EGFR-mt than in EGFR-wild-type LA, which was associated with suppression of chemokine expression. Since this T cell-deserted tumor microenvironment may lead to the refractoriness of ICIs against EGFR-mt LA, we investigated the mechanism by focusing on the regulation of chemokine expression. The expression of C-X-C motif ligand (CXCL) 9, 10 and 11, which constitute a gene cluster on chromosome 4, was suppressed under EGFR signaling. The assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) revealed open chromatin peaks near this gene cluster following EGFR-tyrosine kinase inhibitor (TKI) treatment. The histone deacetylase (HDAC) inhibitor recovered the expression of CXCL9, 10 and 11 in EGFR-mt LA. Nuclear HDAC activity, as well as histone H3 deacetylation, were dependent on oncogenic EGFR signaling. Furthermore, the Cleavage Under Targets and Tagmentation (CUT & Tag) assay revealed a histone H3K27 acetylation peak at 15 kb upstream of CXCL11 after treatment with EGFR-TKI, which corresponded to one of the open chromatin peaks detected by ATAC-seq. The data suggest that EGFR-HDAC axis mediates silencing of the chemokine gene cluster through chromatin conformational change, which might be relevant to the ICI resistance by creating T cell-deserted tumor microenvironment. Targeting this axis may develop a new therapeutic strategy to overcome the ICI resistance of EGFR-mt LA.

SUBMITTER: Sumimoto H

PROVIDER: S-EPMC10060241 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Oncogenic epidermal growth factor receptor signal-induced histone deacetylation suppresses chemokine gene expression in human lung adenocarcinoma.

Sumimoto Hidetoshi H Takano Atsushi A Igarashi Tomoyuki T Hanaoka Jun J Teramoto Koji K Daigo Yataro Y

Scientific reports 20230329 1

Epidermal growth factor receptor (EGFR)-mutated (mt) lung adenocarcinoma (LA) is refractory to immune checkpoint inhibitors (ICIs). However, the mechanisms have not been fully elucidated. CD8<sup>+</sup> T cell infiltration was significantly lower in EGFR-mt than in EGFR-wild-type LA, which was associated with suppression of chemokine expression. Since this T cell-deserted tumor microenvironment may lead to the refractoriness of ICIs against EGFR-mt LA, we investigated the mechanism by focusing ...[more]

PMID: 36991099

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Project description:BackgroundThe nuclear translocation of epidermal growth factor receptor (EGFR) has been considered to play a role in carcinogenesis. However, the relevance of differentially located EGFR proteins in lung cancer remains unclear.MethodsWe examined 161 patients with primary lung adenocarcinoma to detect EGFR expression in lung cancer cells using immunohistochemistry and determined the correlations of EGFR expression with clinical characteristics, EGFR mutations, and survival time. Moreover, we graded complete membranous staining with strong intensity as high membranous EGFR (mEGFR) expression, and nuclear EGFR staining with strong intensity as high nuclear (nEGFR) expression.ResultsThe prevalence of high mEGFR and nEGFR expression in lung adenocarcinoma was 42.86 and 39.13%, respectively. After multivariate analyses, high mEGFR expression was associated with a significantly reduced mortality risk in older patients, those with a history of smoking, and those without brain metastasis (hazard ratio[95% confidential interval], HR[95% CI] = 0.55[0.32~ 0.92]; 0.51[0.26~ 0.98] and 0.56[0.33~ 0.94], in overall survival, respectively). An association between high nEGFR expression and early recurrence was observed in patients with metastasis (HR[95% CI] =1.68[1.05~ 2.68], in progression-free survival). Notably, patients with low mEGFR and low nEGFR expression had the lowest survival rate in cases without brain metastasis (p = 0.018) and with a history of smoking (p = 0.062) and total EGFR (any high mEGFR or nEGFR) expression indicated a more favorable response to platinum-based chemotherapy regardless of EGFR mutations (HR[95% CI] =0.33[0.12-0.92]; adjusted HR[95% CI] = 0.36[0.13~ 1.02] with the use of tyrosine kinase inhibitor).ConclusionsEGFR proteins at different cellular locations in lung adenocarcinoma might influence the biology of cancer cells and are an independent indicator of more favorable prognosis and treatment response.

Project description:Purpose To retrospectively identify the relationship between epidermal growth factor receptor (EGFR) mutation status, predominant histologic subtype, and computed tomographic (CT) characteristics in surgically resected lung adenocarcinomas in a cohort of Asian patients. materials and Methods This study was approved by the institutional review board, with waiver of informed consent. Preoperative chest CT findings were retrospectively evaluated in 385 surgically resected lung adenocarcinomas. A total of 30 CT descriptors were assessed. EGFR mutations at exons 18-21 were determined by using the amplification refractory mutation system. Multiple logistic regression analyses were performed to identify independent factors of harboring EGFR mutation status. The final model was selected by using the backward elimination method, and two areas under the receiver operating characteristic curve (ROC) were compared with the nonparametric approach of DeLong, DeLong, and Clarke-Pearson. Results EGFR mutations were found in 168 (43.6%) of 385 patients. Mutations were found more frequently in (a) female patients (P < .001); (b)those who had never smoked (P < .001); (c)those with lepidic predominant adenocarcinomas (P = .001) or intermediate pathologic grade (P < .001); (e) smaller tumors (P < .001); (f)tumors with spiculation (P = .019), ground-glass opacity (GGO) or mixed GGO (P < .001), air bronchogram (P = .006), bubblelike lucency (P < .001), vascular convergence (P = .024), thickened adjacent bronchovascular bundles (P = .027), or pleural retraction (P < .001); and (g) tumors without pleural attachment (P = .004), a well-defined margin (P = .010), marked heterogeneous enhancement (P = .001), severe peripheral emphysema (P = .002), severe peripheral fibrosis (P = .013), or lymphadenopathy (P = .028). The most important and significantly independent prognostic factors of harboring EGFR-activating mutation for the model with both clinical variables and CT features were those who had never smoked and those with smaller tumors, bubblelike lucency, homogeneous enhancement, or pleural retraction when adjusting for histologic subtype, pathologic grade, or thickened adjacent bronchovascular bundles. ROC curve analysis showed that use of clinical variables combined with CT features (area under the ROC curve = 0.778) was superior to use of clinical variables alone (area under the ROC curve = 0.690). Conclusion CT imaging features of lung adenocarcinomas in combination with clinical variables can be used to prognosticate EGFR mutation status better than use of clinical variables alone. (©) RSNA, 2016 Online supplemental material is available for this article.

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Oncogenic epidermal growth factor receptor signal-induced histone deacetylation suppresses chemokine gene expression in human lung adenocarcinoma.

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Oncogenic epidermal growth factor receptor signal-induced histone deacetylation suppresses chemokine gene expression in human lung adenocarcinoma.

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