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.

Original languageEnglish
Pages (from-to)7631-7643
Number of pages13
JournalOncotarget
Volume9
Issue number7
DOIs
Publication statusPublished - Jan 26 2018

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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

  • Epidermal growth factor receptor
  • Lung cancer
  • Macrophages
  • Myeloid derived suppressor cells
  • NF-kappa B

ASJC Scopus subject areas

  • Oncology

Cite this

@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

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VL - 9

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SN - 1949-2553

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