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T. Yukawa



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.05 - EGFR signaling effects on NK cell-mediated cytotoxicity via NKG2D ligands-NKG2D interaction in non-small cell lung cancer cells (ID 2221)

      10:55 - 11:00  |  Author(s): T. Yukawa

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR-tyrosine kinase inhibitor Gefitinib interrupts signaling through the EGFR in non-small-cell lung cancer (NSCLC) cells with EGFR driver mutation and has shown impressive activity in terms of clinical benefit for patients with NSCLC, however, almost all patients develop resistance to this drug. Although much research is focusing on the mechanisms of drug resistance in tumor cell, the role of EGFR signaling in tumor escape from the host immune system is poorly understood. NK cell activity is promoted via NK group 2, member D (NKG2D) on NK cells. The engagement between NKG2D and its ligands enhances cell-mediated cytotoxicity and cytokine production against transformed cells. Both MHC class I-related chain A and B (MICA/B) and UL16 binding protein (ULBP)s are expressed by intestinal epithelial and at low levels also by other non-malignant cell types. Primary tumor cells and tumor cell lines frequently express NKG2D ligands, but the mechanisms responsible for the induction of NKG2D ligands during oncogenesis are also poorly understood. Here we demonstrate Gefitinib downregulates NK group 2 member D (NKG2D) ligand MICA/B and ULBPs, resulting in attenuation of NK cell-mediated cytotoxicity in NSCLC cells.

      Methods
      Possible influences of Gefitinib on expressions of MHC class I, MICA/B and ULBP1-3 in 5 NSCLC cell lines (A549, PC-9, RERF-LC-KJ, RERF-LC-AI, and LC2/ad) were investigated by flow cytometry. We also assessed whether genetic silencing of EGFR using siRNA of EGFR affected on the expression of NKG2D ligands. To ask the main downstream pathway of EGFR regulating the expression of NKG2D ligands, the cells were treated with PI3K-AKT inhibitor LY294002 or MEK inhibitor PD98059 then the expression of NKG2D ligands was analyzed. NK cell-mediated cytotoxicity against cancer cells was assessed by [51]Cr release assay or flow cytometry based CD107a degranulation assay.

      Results
      Gefitinib downregulated NKG2D ligands in NSCLC cell lines. In line with these results, siRNA-mediated silencing of EGFR downregulated the expression of NKG2D ligand. Among the major downstream pathways activated by EGFR signaling, the expression of NKG2D ligands was mainly regulated by the PI3K-AKT pathway. Treatment with EGF promoted MICA/B expression in 2 of 5 cell lines, while EGF decreased MICA/B in 1 of 5 cell lines. These observations further emphasize that EGFR signaling is one of the major pathways regulating the expression of NKG2D ligands in NSCLC cells. As expected, inhibition of EGFR signaling-downregulated NKG2D ligands attenuated NK cell-mediated cytotoxicity.

      Conclusion
      We conclude that EGFR signaling directly regulates the expression of NKG2D ligands and that this may influence the recognition of tumor cells by the innate immune system.

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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-010 - Heterogeneity of biomarkers between the primary tumor and the metastatic lymph nodes in non-small cell lung cancer (ID 1203)

      11:36 - 11:50  |  Author(s): T. Yukawa

      • Abstract

      Background
      Recently, the personalized treatments for non-small cell lung cancer (NSCLC) have progressed with the understanding of the biology and the molecular mechanisms of the tumor. Treatment strategy is determined based on the biomarker profiles examined with the primary tumor tissue or the metastatic lymph nodes. However, because tumor cells acquire the metastatic phenotype through the process of clonal evolution occurring during the tumor progression, there could be the heterogeneity of the biomarker profiles between the primary tumor and the metastatic lesions. The aim of this study was to investigate the heterogeneity of the biomarkers between the primary tumor and the metastatic lymph nodes, and to evaluate the clinical significance of its discordancy.

      Methods
      Seventy-two patients of NSCLC with lymph node metastases who underwent complete resection with systematic lymph node dissection between 2004 and 2010 were studied. The study was conducted with the approval of the institutional ethics committee. Immunohistochemical analysis of ERCC1 and VEGF and the mutation analysis of EGFR were performed with the paraffin-embedded tissue of both the primary tumor (PT) and the metastatic lymph nodes (LN).

      Results
      There were 47 male and 25 female, with the median age of 69.4 years. Thirty-eight patients had adenocarcinoma, 23 had squamous cell carcinoma, and 11 had other histologic types of NSCLC. Twenty-nine patients had N1 disease, and 43 had N2. Median observation period was 35.7 months. The 5-year overall survival rate of 72 patients was 38.0%, with 53.2% in N1 cases and 28.8% in N2 cases. ERCC1 was positive in 41.7% of PT and 58.3% of LN. There were 34 cases (47.2%) with the discordant expression of ERCC1. VEGF was positive in 66.7% of both PT and LN, whereas 32 cases (44.4%) were discordant. EGFR mutation was detected in 31.9% of PT and 18.1% of LN. There were 10 cases (13.9%) with discordant mutation status. All 10 cases had mutant EGFR in PT, whereas EGFR mutation was not found in LN. Of the 49 patients with EGFR mutation-negative in PT, none showed mutations in LN. There were no differences in relapse-free survival and overall survival among the biomarker profile groups. Among patients who had negative ERCC1 in PT or LN, overall survival was significantly better in patients who received platinum-based chemotherapy perioperatively compared with that in patients who did not. However, there were no differences in patients with positive ERCC1 in PT or LN. Seventeen patients who had mutant EGFR in PT were treated with gefitinib. The responses were CR in 4, PR in 7, SD in 2, and PD in 4, with the response rate of 64.7% and the disease control rate of 76.5%. All the nine patients who had mutant EGFR in both PT and LN showed disease control, whereas 4 out of 8 patients who had mutant-negative EGFR in LN showed PD.

      Conclusion
      It should be noted that discordancy of biomarker profiles between PT and LN was not a few. Understanding the heterogeneity of biomarkers would be essential for the establishing the personalized treatments for NSCLC.