Author of

• 18502

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  P3.02c - Poster Session with Presenters Present (ID 472)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 18561

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    P3.02c-059 - CD70 Immune Checkpoint Ligand is Associated with Epithelial-To-Mesenchymal Transition in Non-Small Cell Lung Cancer (ID 4317)

    14:30 - 14:30  |  Author(s): F. Fauvet
    • Abstract

    Background:
    Recent advances in the modulation of immune checkpoints (ICPs) or their ligands (ICPLs) indicate their role in anti-tumor immunity and in mediating durable cancer regressions in NSCLC and other cancers. Epithelial-to-mesenchymal transition (EMT) enables the reprogramming of polarized epithelial cells towards a mesenchymal phenotype with migratory and invasive properties. EMT promotes cancer cell plasticity and favors tumor adaptability to encountered selective pressures. We hypothesize that EMT represents an escape mechanism to immune-surveillance.
    
    Methods:
    ICPLs gene expression patterns were analyzed in silico in 129 NSCLC cell lines (CCLE) in relation to their EMT status (Mak. CCR, 2015). These observations were validated using the TCGA RNAseq data available for lung adenocarcinomas (n=488) and squamous-cell carcinomas (n=501) and the GSE41271 dataset (n=275 NSCLC tumors). In vitro, CD70 expression was evaluated by FACS in (1) epithelial Vs mesenchymal lung cancer cell lines, (2) HCC44 cells (mesenchymal) that underwent CRISPR/Cas9-mediated knock out of ZEB1 and in (3) H3255 (epithelial) that overexpress SNAIL. The expression of CD70 and markers of immune infiltrate was assessed by immunohistochemistry in a cohort of 132 NSCLC.
    
    Results:
    Unsupervised hierarchical cluster analysis revealed that expression of CD70 was significantly associated with the mesenchymal status in NSCLC cell lines (p < 0.001). These results were confirmed in silico in all three datasets of NSCLC samples. We identified the E-box sequence CANNTG in the CD70 gene promoter, suggesting the possible regulation of CD70 by ZEB1 and/or SNAIL. CD70 expression was increased in mesenchymal Vs epithelial NSCLC cell lines. Overexpression of SNAIL in H3255 cells did not result in the acquisition of mesenchymal properties or in changes in CD70 expression. CRISPR/Cas9-mediated knock out of ZEB1 was successful in HCC44 cells and resulted in increased expression of E-cadherin and EpCAM when compared to the control. The analysis of CD70 expression in this model will be presented. We found increased CD70 positivity in sarcomatoid tumors compared to non-sarcomatoid NSCLC. Of note, the expression of CD70 in sarcomatoid tumors was limited to the mesenchymal compartment and co-localized with ZEB1. It is known that CD70 by tumor cells can facilitate evasion of the immune system. The analyses of tumor immune infiltrate markers and T-cell exhaustion in a cohort of 18 lung sarcomatoid tumors will be presented.
    
    Conclusion:
    The association of EMT and CD70 in lung tumors may play an important role of this interaction in immune scape. CD70 might represent a relevant target in sarcomatoid lung tumors.