Author of

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  FP10 - Small Cell Lung Cancer/NET (ID 231)

  • Event: WCLC 2020
  • Type: Posters (Featured)
  • Track: Small Cell Lung Cancer/NET
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 36121

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    FP10.02 - Investigating the Immunophenotype of Small Cell Lung Cancer to Improve Immunotherapeutic Targeting (ID 1686)

    00:00 - 00:00  |  Author(s): Louis Irving
    • Abstract
    • Presentation
    • Slides

    Introduction
    

    Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer and although most patients initially respond to platinum-based chemotherapy, resistance rapidly develops. Immunotherapy has promise in the treatment of lung cancer, however SCLC patients exhibit poor overall responses. This highlights the necessity for alternative treatment approaches. Recently, SCLC has been divided into four subtypes based on the expression of key transcription factors, ASCL1, NEUROD1, POU2F3 and YAP1. Though it has been speculated that these subtypes may respond differentially to therapeutic interventions, response to cytotoxic immune cell killing has not been investigated.

    Methods
    

    We have investigated the immune microenvironment (IM) profiles of human SCLC patients on freshly obtained endobronchial ultrasound biopsies. We characterized the IM through antibody panels (flow cytometry) and unbiased hierarchal clustering (single-cell sequencing). Immune cell signatures were also interrogated in publicly available human SCLC datasets. Subcutaneous transplantation studies utilizing syngeneic SCLC cell lines were performed to functionally validate the role of cytotoxic immune cell populations. Tumor growth, metastatic dissemination and the activation of CD8⁺ T and natural killer (NK) cells were evaluated by histology and flow cytometry.

    Results
    

    Transcriptomic analysis of treatment naïve human SCLC samples revealed heterogeneous immune checkpoint and cytotoxic signature profiles. We identified that immune cell infiltration scores stratified the four subtypes of SCLC, suggesting immunotherapeutic targeting may be prognostic in some patient cohorts. To functionally evaluate the role of cytotoxic immune cells in the surveillance of SCLC, we demonstrated that the absence of NK cells, but not CD8⁺ T cells, significantly enhanced metastatic dissemination of SCLC in vivo.

    Conclusion
    

    These proof-of-principle findings provide a rationale for exploiting the anti-tumor functions of NK cells in the treatment of SCLC patients. Critically, the distinct IM profiles of SCLC subtypes reveal an unappreciated level of heterogeneity that warrants further investigation in the stratification of patients for immunotherapy.

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