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L. Rozeboom



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    MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 05.14 - Differential Expression of IFN-Stimulating DNA Sensors STING and cGAS in Lung Cancer Subtypes (ID 9578)

      15:45 - 17:30  |  Author(s): L. Rozeboom

      • Abstract
      • Presentation
      • Slides

      Background:
      STING is a protein that promotes type I IFN production (IFNα/β) essential for activation of dendritic cells and antigen presentation and priming of T-cells. The cytoplasmic DNA sensor cGAS (cGAMP Synthase) is able to detect tumor DNA, and in response will synthesize cGAMP. cGAMP binds STING specifically, resulting in production of type I IFN. STING is therefore referred to as an adaptor protein essential for immune signaling following detection of tumor DNA. Analysis of the TCGA database indicates decreased survival in lung adenocarcinoma patients lacking STING expression. STING expression is decreased in tumor tissues and can be lost as the tumor progresses. One reported mechanism of loss of STING or cGAS in tumors is due to hypermethylation, a common occurrence in lung cancer. Agonists of STING show potent immune response and are currently in clinical trials. Importantly, recent studies show that expression of STING and cGAS proteins are essential for response to PD-1:PD-L1 blockade.

      Method:
      Section not applicable

      Result:
      We analyzed 55 NSCLC and 39 SCLC cell lines, and 317 NSCLC and 78 SCLC tissues for STING and cGAS expression using immunohistochemistry. 14/55 (25.45%) NSCLC cell lines and 25/39 (64.10%) SCLC cell lines showed no STING expression. Separated in to adenocarcinoma (AC) and squamous cell carcinoma (SCC) subsets, STING expression in AC shows loss of STING as tumor stage increases (Positive: 70% Stage I, 65% Stage II, 52% Stage III, 40% Stage IV, 71% total; n=156) while STING expression is low at all stages of SCC (Positive: 29% Stage I, 18% Stage II, 36% Stage III, 13% Stage IV, 27% total; n=161). SCLC tissues stained showed widespread loss of STING (Positive: 40% Stage I, 27% Stage II, 31% Stage III, 100% Stage IV, 37.18% total, n=78). Expression of cGAS was higher in AC (94%) than SCC (75%) and showed no correlation with stage. TCGA analysis of STING methylation shows hypermethylation in AC (0.15- ± 0.13 tumor vs 0.05 ± 0.02 normal, n=422) and SCC (0.23 ± 0.16 tumor vs 0.04 ± 0.03 normal, n=359). cGAS shows slight methylation in AC (0.05 ± 0.07 tumor vs 0.05 ± 0.01 normal, n=422) but a large increase in SCC (0.19 ± 0.24 tumor vs 0.04 ± 0.01 normal, n=359).

      Conclusion:
      This study indicates drastic differences in STING and cGAS expression in AC, SCC, and SCLC. Differential expression of these proteins could impact the efficacy of STING agonists, radiation therapy, and immunotherapy in lung cancer.

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    OA 07 - Biomarker for Lung Cancer (ID 659)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 07.06 - Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions (ID 9102)

      15:45 - 17:30  |  Author(s): L. Rozeboom

      • Abstract
      • Presentation
      • Slides

      Background:
      Cancers are composed of heterogeneous cell populations in terms of somatic mutations and dysregulated signaling pathways. We hypothesized that such heterogeneity, together with selection advantages conferred by distinct microenvironments, may contribute to tumor evolution and metastatic patterns.

      Method:
      We collected tumor specimens and non-cancer tissues from treatment-naïve autopsied patients to study the innate genetic evolution and spatial heterogeneity by RNA-sequencing. Our cohort consists of four NSCLC patients and one SCLC patient. Each patient had 5 – 9 primary and metastatic lesions, including metastases to lung, liver, colon (distant metastases), visceral or parietal pleura (pleural metastases), and intra- or extra-thoracic lymph nodes (lymph nodes metastases). Comprehensive data analyses were performed, including gene expression / pathway analyses and fusions / somatic variants detection.

      Result:
      Global unsupervised clustering analysis of expression data reveals that lesions from each patient clustered together, indicating that tumor cells themselves have greater effects on the gene expression signature than the microenvironment. Pathway analyses in individual patients revealed that the primary lesion is distinct from metastatic lesions in NSCLCs (Figure-left). For the SCLC patient, distant metastases and lymph node metastases clustered according to different parts of the primary tumor (Figure-right). Pathway analyses also revealed that cell-cycle, DNA replication, RNA polymerase, and spliceosome-related pathways are upregulated, while immune-related pathways are downregulated in all metastatic patterns compared with primary lesions. In particular, we observed that multiple immune-related pathways, related to NK cells and T-cells, were downregulated in pleural metastases. Detection of fusions / somatic variants identified the KIF5B-RET fusion as a founder mutation in a never-smoking adenocarcinoma patient. Notch signaling was upregulated, in this patient, in all metastatic lesions but not the primary site.Figure 1



      Conclusion:
      These data demonstrate the similarity and the heterogeneity between primary and metastatic lesions in lung cancer patients. In addition, we identified the correlation between tumor heterogeneity and metastatic patterns.

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