S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB

// Po-Hao Feng 1, 2 , Chih-Teng Yu 3 , Kuan-Yuan Chen 1, 4 , Ching-Shan Luo 1 , Shen Ming Wu 1 , Chien-Ying Liu 3 , Lu Wei Kuo 1 , Yao-Fei Chan 3 , Tzu-Tao Chen 1 , Chih-Cheng Chang 1 , Chun-Nin Lee 1 , Hsiao-Chi Chuang 5 , Chiou-Feng Lin 6 , Chia-Li Han 7 , Wei-Hwa Lee 8 and Kang-Yun Lee 1, 2 1 Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan 2 Division of Thoracic Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 3 Division of Pulmonary Medicine, Department of Internal Medicine, Chang Gung Medical Foundation Linko Branch, Taoyuan, Taiwan 4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan 6 Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 7 Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan 8 Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan Correspondence to: Kang-Yun Lee, email: lee4949@ms41.hinet.net 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 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 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.