摘要

Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. Conclusions: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the noncanonical NF-κB RELB pathway. Methods: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.
原文英語
頁(從 - 到)7631-7643
頁數13
期刊Oncotarget
9
發行號7
DOIs
出版狀態已發佈 - 一月 26 2018

指紋

Protein-Tyrosine Kinases
Macrophages
Microarray Analysis
Blood Cells
Alveolar Macrophages
Coculture Techniques
RNA Interference
Myeloid-Derived Suppressor Cells
Adenocarcinoma of lung
Disease-Free Survival
Lung Neoplasms
Up-Regulation
Cell Count
Western Blotting
Tissue Donors
T-Lymphocytes
Mutation
Therapeutics
Genes
Neoplasms

Keywords

  • lung cancer
  • myeloid derived suppressor cells
  • epidermal growth factor receptor
  • macrophages
  • NF-kappa B

ASJC Scopus subject areas

  • Oncology

引用此文

@article{f34db6a2492946d498b3137b5061d2b6,
title = "S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: The role of RELB",
abstract = "Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. Conclusions: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the noncanonical NF-κB RELB pathway. Methods: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.",
keywords = "Epidermal growth factor receptor, Lung cancer, Macrophages, Myeloid derived suppressor cells, NF-kappa B, lung cancer, myeloid derived suppressor cells, epidermal growth factor receptor, macrophages, NF-kappa B",
author = "Feng, {Po Hao} and Yu, {Chih Teng} and Chen, {Kuan Yuan} and Luo, {Ching Shan} and Wu, {Shen Ming} and Liu, {Chien Ying} and Kuo, {Lu Wei} and Chan, {Yao Fei} and Chen, {Tzu Tao} and Chang, {Chih Cheng} and Lee, {Chun Nin} and Chuang, {Hsiao Chi} and Lin, {Chiou Feng} and Han, {Chia Li} and Lee, {Wei Hwa} and Lee, {Kang Yun}",
year = "2018",
month = "1",
day = "26",
doi = "10.18632/oncotarget.24146",
language = "English",
volume = "9",
pages = "7631--7643",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "7",

}

TY - JOUR

T1 - S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma

T2 - The role of RELB

AU - Feng, Po Hao

AU - Yu, Chih Teng

AU - Chen, Kuan Yuan

AU - Luo, Ching Shan

AU - Wu, Shen Ming

AU - Liu, Chien Ying

AU - Kuo, Lu Wei

AU - Chan, Yao Fei

AU - Chen, Tzu Tao

AU - Chang, Chih Cheng

AU - Lee, Chun Nin

AU - Chuang, Hsiao Chi

AU - Lin, Chiou Feng

AU - Han, Chia Li

AU - Lee, Wei Hwa

AU - Lee, Kang Yun

PY - 2018/1/26

Y1 - 2018/1/26

N2 - Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. Conclusions: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the noncanonical NF-κB RELB pathway. Methods: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

AB - Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. Conclusions: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the noncanonical NF-κB RELB pathway. Methods: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

KW - Epidermal growth factor receptor

KW - Lung cancer

KW - Macrophages

KW - Myeloid derived suppressor cells

KW - NF-kappa B

KW - lung cancer

KW - myeloid derived suppressor cells

KW - epidermal growth factor receptor

KW - macrophages

KW - NF-kappa B

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U2 - 10.18632/oncotarget.24146

DO - 10.18632/oncotarget.24146

M3 - Article

VL - 9

SP - 7631

EP - 7643

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 7

ER -