Abstract 207P
Background
Immune checkpoint inhibitors (ICIs) pushed therapeutic strategy of NSCLC into a new era. Nevertheless, the clinical benefit of ICI therapy in EGFR-driven NSCLC patients, especially patients resistant to EGFR-TKI was unsatisfactory. Immunosuppressive tumor microenvironment (TME) after EGFR-TKI treatment proved huge influence on the efficacy of ICIs. Investigation of the mechanism underlying suppressive TME and exploration of its potential intervention was the urgent requirement for EGFR-TKI resistant NSCLC research.
Methods
ZEB2 expression in NSCLC cell lines and patients’ samples were assessed utilizing qRT-PCR, western blotting, and IHC. The effect of EGFR-TKI resistance and ZEB2 on TAMs polarization were investigated via qRT-PCR of M1/M2 biomarkers and flow cytometry. The modulation of ZEB2 on cytokines’ secretion was evaluated through qRT-PCR, ELISA and MSD. The direct influence of ZEB2 on promoter regions of cytokines was explored by dual luciferase reporter assay. The regulation of signaling pathway on ZEB2 was analyzed by correlative analysis, the results were consolidated using western blotting. Mouse models were used to further confirm the influence of EGFR-TKI resistance and ZEB2 on TAMs polarization.
Results
EGFR-TKI resistance induced M2 polarization and inhibited M1 polarization of TAMs, which was critical for the formation of immunosuppressive TME. ZEB2 was upregulated in EGFR-TKI resistant NSCLC in vitro, in vivo and in silicon. ZEB2 upregulation could induce M2 polarization and impede M1 polarization of TAMs, demonstrating its essential role in the influence of EGFR-TKI resistant NSCLC on TAMs polarization. Besides, ZEB2 overexpression was dependent on PI3K-Akt pathway which was upregulated after EGFR-TKI resistance in NSCLC. Finally, ZEB2's regulation on TAMs polarization was associated with cytokines’ secretion. Apart from its inducement on TGF-β1 secretion, ZEB2 directly bound to the promoter region of CSF-1 to elevate its secretion.
Conclusions
ZEB2, which was upregulated in EGFR-TKI resistant NSCLC on a PI3K-Akt dependent manner, could induce M2 polarization and hinder M1 polarization via elevating the secretion of CSF-1 and TGF-β1.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
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