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

Keywords

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

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'S100A9<sup>+</sup> MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: The role of RELB'. Together they form a unique fingerprint.

  • Cite this