Author of

• 25941

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  P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall

  • 26978

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    P2.04-03 - NF-κB and HIF-1α Play Important Roles in Regulating PD-L1 Expression by EGFR or KRAS Mutants in Non-Small Cell Lung Cancer Cells (ID 12672)

    16:45 - 18:00  |  Author(s): YONG Li
    • Abstract

    Background
    

    Programmed death ligand 1 (PD-L1) is expressed in various human tumors and is of critical importance for the immune escape of tumor cells. Some driver gene mutations including EGFR and KRAS have been reported to be involved in PD-L1 expression regulation. However, the potential role and precise mechanism of EGFR and KRAS mutants in PD-L1 expression regulation in non-small cell lung cancer (NSCLC) remain obscure.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    The expression levels of PD-L1 and key molecules of EGFR and KRAS signaling pathways were examined in 11 NSCLC cells with wild-type or mutant EGFR and KRAS genes. Additionally, ectopic expression or depletion of EGFR or KRAS mutants and pharmacological inhibitors of MEK/ERK, PI3K/AKT, IκBα, and HIF-1α were employed to elucidate the effects of activation or inhibition of EGFR or KRAS pathway on PD-L1 expression regulation in NSCLC cells. The effects of pathway inhibitors on tumorigenesis and PD-L1 expression of EGFR or KRAS-mutated NSCLC cells were also examined using xenograft mouse model, Furthermore, the correlations between EGFR and KRAS status and protein levels of HIF-1α and PD-L1 were analyzed in 97 NSCLC tissues.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Examination of the EGFR and KRAS signaling cascades in NSCLC cells revealed an apparent association of PD-L1 overexpression with activation of MEK/ERK and PI3K/AKT pathways, especially with increased protein levels of p-IκBα and HIF-1α. Notably, ectopic expression or depletion of EGFR or KRAS mutants and administration of EGFR or KRAS pathway inhibitors showed important interplay and cooperation between NF-κB and HIF-1α in PD-L1 expression regulation in NSCLC cells. Furthermore, administration of EGFR or KRAS pathway inhibitors significantly inhibited xenograft tumor growth and PD-L1 expression of NSCLC cells in nude mice. Moreover, NSCLC tissues with positive HIF-1α staining presented significantly increased positive rate of PD-L1 expression compared with tissues scored HIF-1α negative (49.1% vs. 20.5%, P = 0.003). NSCLC tissues with EGFR or KRAS mutants showed obviously elevated expression levels of HIF-1α and PD-L1 compared with tissues carrying wild-type EGFR and KRAS genes (68.4% vs. 43.4%, P = 0.018 and 50.0% vs. 28.3%, P = 0.035, respectively).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Taken together, both EGFR and KRAS mutants were identified to regulate PD-L1 expression via signaling effectors, NF-κB and HIF-1α, suggesting the correlation between driver gene mutations and tumor immune escape in NSCLC.

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