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Matt Ritchie



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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
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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): Matt Ritchie

      • 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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    P62 - Tumor Biology and Systems Biology - Basic and Translational Science - Metabolomics (ID 200)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P62.05 - Identifying Therapeutic Approaches to Treat KEAP1-Mutant Lung Adenocarcinoma (ID 1645)

      00:00 - 00:00  |  Author(s): Matt Ritchie

      • Abstract
      • Slides

      Introduction

      The most frequently altered gene in lung adenocarcinoma (ADC) is the KRAS oncogene. Currently, there are no effective treatments to target KRAS-mutant ADC. Loss-of-function in Kelch-like ECH-associated protein 1 (KEAP1) is co-mutated in 18% of KRAS-mutant ADC and is mutually exclusive with inactivating mutations in Tumor protein 53 (TP53). KEAP1 is a negative regulator of the transcription factor NRF2, which regulates cellular antioxidant and metabolic pathways. Metabolic dysregulation is considered a hallmark of cancer cells, which utilize anaerobic glycolysis and anabolic glucose metabolism in preference to aerobic oxidative phosphorylation in a phenomenon termed the Warburg effect.

      Methods

      We interrogated the consequences of Keap1 loss in KrasG12D-induced ADC using conditional genetically engineered mouse models (GEMMs). To examine metabolic features unique to Keap1-mutant ADC, GEMMs with KrasLSL-G12D/+ alone or carrying either a p53flox/flox allele (Kras/p53), Keap1flox/flox allele (Kras/Keap1) and/or Lkb1flox/flox allele (Kras/Lkb1) were investigated. Key features of tumor development, immune microenvironment and metabolism were investigated in the spontaneous lung tumors.

      Results

      Major alterations in glycolytic function were identified as unique features of Keap1 inactivation in lung adenocarcinomas carrying oncogenic activation of Kras. Critically, hallmarks of altered metabolism were identified in the peripheral blood of mice bearing Keap1-deficient lung adenocarcinoma. Inhibiting these metabolic pathways in vitro and in vivo resulted in the identification of Keap1-specific therapeutic modalities.

      Conclusion

      Loss of Keap1 function in Kras-mutant ADC creates a pro-oncogenic metabolic environment driving lung tumorigenesis. Targeting metabolic dependency in KRAS-mutant tumours may provide a unique method of treating this aggressive subset of lung ADC.

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