S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB
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Po-Hao Feng1,2, Chih-Teng Yu3, Kuan-Yuan Chen1,4, Ching-Shan Luo1, Shen Ming Wu1, Chien-Ying Liu3, Lu Wei Kuo1, Yao-Fei Chan3, Tzu-Tao Chen1, Chih-Cheng Chang1, Chun-Nin Lee1, Hsiao-Chi Chuang5, Chiou-Feng Lin6, Chia-Li Han7, Wei-Hwa Lee8 and Kang-Yun Lee1,2
1Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
2Division of Thoracic Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
3Division of Pulmonary Medicine, Department of Internal Medicine, Chang Gung Medical Foundation Linko Branch, Taoyuan, Taiwan
4Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
5School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
6Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
7Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
8Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
Kang-Yun Lee, email: [email protected]
Keywords: lung cancer; myeloid derived suppressor cells; epidermal growth factor receptor; macrophages; NF-kappa B
Received: September 06, 2017 Accepted: January 03, 2018 Published: January 10, 2018
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 non-canonical 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.
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