Author of

• 30446

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  P1.01 - Advanced NSCLC (ID 158)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall

  • 30516

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    P1.01-60 - Prognostic Impact of PD-L1 Expression on EGFR Tyrosine Kinase Inhibition in Lung Adenocarcinoma (ID 1506)

    09:45 - 18:00  |  Author(s): Bhumsuk Keam
    • Abstract
    • Slides

    Background
    

    EGFR tyrosine kinase inhibitors (TKIs) are recommended as first-line systemic therapy for advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. The programmed death-ligand 1 (PD-L1) expression on tumor cells has emerged as a prognostic marker after surgical resection in various tumors including NSCLC. This study investigated the predictive value of PD-L1 expression on the duration of treatment and the emergence of T790M mutation in patients treated with EGFR-TKIs.

    Method
    

    We retrospectively enrolled 109 patients with advanced NSCLC who had been treated with EGFR-TKIs as first-line systemic treatment at Seoul National University Bundang Hospital and Seoul National University Hospital between December 2012 and October 2018. Patients without sensitizing EGFR gene mutations (exon 19 deletion, exon 21 L858R, and L861Q) were excluded. The PD-L1 expression on tumor cells was scored using two immunohistochemistry assays (22C3 or SP263). The Kaplan-Meier survival estimation and log rank test were used for survival analyses.

    Result
    

    Among the 109 patients (Median age 65; Male:Female = 37:72), 17 (15.6%), 37 (33.9%) and 55 (50.5%) patients had strong (≥50%), weak (1%-49%), and negative (<1%) PD-L1 expression, respectively. In univariate analysis, the median time-to-treatment failure (TTF) of EGFR-TKI treatment was 7.6 months in strong expression, 14.2 months in weak expression, and 13.0 months in negative expression (log-rank; Strong vs. Weak, P=0.008; Strong vs. Negative, P=0.031). There was no statistically significant difference of TTF between the patients with weak expression and negative expression (log-rank, p=0.191). After adjustment of age, sex, and smoking status, strong PD-L1 expression remained as a significant predictor of short TTF (hazard ratio [HR] for strong vs. weak, 2.68; 95% CI, 1.35-5.33; P=0.005). The detection rates of T790M mutation after EGFR-TKI failure were similar in three groups (23.53% in strong, 29.73% in weak, and 32.73% in negative PD-L1 expression; P=0.478). In patients treated with 3rd generation EGFR-TKIs (n=35), there was no statistically significant difference of TTF according to PD-L1 expression (p=0.889).

    Figure. Kaplan-Meier survival curve for TTF of 1st line EGFR-TKIs according to PD-L1 expression

    

    Conclusion
    

    Strong PD-L1 expression of tumor might be a surrogate indicator of poor response to EGFR-TKIs in NSCLC patients with sensitizing EGFR mutations.

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• 30943

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  P2.04 - Immuno-oncology (ID 167)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Immuno-oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30991

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    P2.04-42 - PD-L1-Mediated Enhancement of Hexokinase 2 Expression Is Inversely Related to T-Cell Effector Gene Expression in Non-Small-Cell Lung Cancer (ID 2240)

    10:15 - 18:15  |  Author(s): Bhumsuk Keam
    • Abstract

    Background
    

    The PD-1/PD-L1 pathway contributes to the metabolic reprogramming of immune cells and tumor cells. However, the mechanism by which PD-L1 regulates glycolysis in human cancer and the relationship between PD-L1 expression, glycose metabolism and anti-tumor immune response remain unclear. We addressed these issues in human non-small-cell lung cancer (NSCLC).

    Method
    

    Changes in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1^low and PD-L1^high NSCLC cells after transfection or knockdown of PD-L1, respectively. RNA seq and gene set enrichment analyses (GSEA) was also performed. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA).

    Result
    

    Transfecting PD-L1 in PD-L1^low cells enhanced hexokinase-2 (HK2) expression, lactate production, and extracellular acidification rates, but minimally altered GLUT1 and PKM2 expression and oxygen consumption rates. Consistently, GSEA revealed that the glycolytic pathway was enhanced in PD-L1^low cells after PD-L1 transfection. By contrast, knocking-down PD-L1 in PD-L1^high cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Immunohistochemistry revealed that PD-L1 expression was positively correlated with HK2 expression in NSCLC tissues from patients (p<0.001). In TCGA analyses, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p<0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274^high rather than CD274^low group. Consistent with this, there were fewer CD8⁺ T-cells in PD-L1^positive/HK2^high tumors compared to PD-L1^positive/HK2^low tumors in squamous cell carcinoma.

    Conclusion
    

    PD-L1 enhances glycolysis in NSCLC by upregulating HK2, which might dampen anti-tumor immunity. PD-L1 may contribute to NSCLC oncogenesis by inducing metabolic reprogramming and immune checkpoint pathway.