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K.W. Ng



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    MA 10 - Immunotherapy I (ID 664)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 10.09 - Increased T Follicular Helper Cell Infiltration in Lung Adenocarcinoma Tertiary Lymphoid Organs (ID 8487)

      11:00 - 12:30  |  Author(s): K.W. Ng

      • Abstract
      • Presentation
      • Slides

      Background:
      T follicular helper cells (Tfh) are an antigen-experienced CD4+ T cell subset that have been found to play crucial roles in the development of humoral immunity. In particular, their presence in the B cell-rich germinal centre of secondary and tertiary lymphoid tissue aids in B cell maturation through selection of B cells producing high-affinity antibodies. Tfh cells have known roles in autoimmune disease and B cell malignancies; however, their role in many solid tumours, including those of the lung, remains unclear.

      Method:
      We analyzed 83 paired tumour-normal lung adenocarcinoma samples from the BC Cancer Agency (BCCA) as well as 576 unpaired samples from The Cancer Genome Atlas (TCGA). Relative immune cell content was obtained from gene expression data using a linear support vector regression deconvolution approach (CIBERSORT). Spatial positioning of B and T cells within selected tumour sections was examined through IHC. The impact of Tfh infiltration on patient survival was analyzed using a Cox Proportional Hazard model.

      Result:
      T follicular helper cells are increased in tumour tissue, accompanied by global upregulation of Tfh markers PDL1 and CXCR5 in both the BCCA and TCGA cohorts. Histological analysis revealed localization of Tfh cells within tertiary lymphoid organs, with direct contact with B cells in the follicular zone observed. Importantly, Tfh recruitment appears to be an early event in tumour development and a function of neoantigen exposure, indicative of an active anti-tumour response rather than a result of chronic inflammation of the tumour microenvironment.

      Conclusion:
      T follicular helper cells are required for B cell maturation and subsequent antibody responses. As such, it is not surprising that Tfh infiltration in tumour-resident ectopic lymphoid structures correlates with patient survival in various cancer types. Given the importance of tumour-specific antibody responses in natural and therapeutic immunity, further investigation of Tfhs may show prognostic utility and be a marker of early-stage lung tumours.‚Äč

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    MA 15 - Lung Cancer Biology II (ID 670)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 15.12 - Expanding the Lung Small RNA Transcriptome: Discovery of Unannotated microRNAs with Roles in Development and Tumourigenesis (ID 9100)

      15:45 - 17:30  |  Author(s): K.W. Ng

      • Abstract
      • Presentation
      • Slides

      Background:
      MicroRNAs (miRNAs) are key regulators of gene expression. They participate in many biological and pathological processes, from organ development to malignant transformation. Their functions are widely conserved, involving post-transcriptional silencing of gene expression. Over 2500 mature miRNA sequences have been identified in humans; however, recent studies have showed that the number of annotated miRNAs represent only a fraction of the total pool of existing miRNAs, suggesting that there are still many potentially undiscovered biologically relevant miRNAs encoded by the human genome. Here, we perform a comprehensive study to identify novel miRNA sequences expressed in non-malignant lung tissues, as well as samples from developmental stages and pathological conditions.

      Method:
      A total of 422 samples were included in this analysis. First, 209 non-malignant samples from two cohorts (BCCA, n=118 and TCGA, n=91) were analyzed using our customized small RNA sequence analysis pipeline. Sequence reads were aligned to the hg38 build of the human genome (STAR algorithm) and novel miRNAs were predicted using mirDeep2. The results were compared to miRNA databases and further filtered by abundance and for miRNA-compatible structure. The same procedure was applied to matched tumours (n=209) and samples derived from fetal lungs (n=4). The biological relevance of the novel sequences was investigated by assessing their expression in tumours and fetal samples, together with gene target prediction and tissue-specific protein-protein interaction (PPI) network analyses using IID.

      Result:
      Our study discovered the expression of 294 novel miRNA sequences in lung tissue, significantly expanding the current human lung miRNA transcriptome. These novel miRNAs showed similar nucleotide composition and genomic distribution compared to known miRNAs, providing additional evidence of their miRNA-compatible nature. Interestingly, a subset of these miRNAs were also found to be expressed in tumour and fetal samples, indicating that they might play important roles in organ development and tumourigenesis. Likewise, target prediction analysis revealed that these novel miRNAs are involved in key cellular processes including cell proliferation, migration and survival, as well as pathways known to be deregulated in cancer, as comprehensively analyzed using pathDIP.

      Conclusion:
      Our study has significantly expanded the lung small RNA transcriptome, and provided evidence that the novel miRNAs are involved in molecular networks relevant to lung biology and pathology. These results also highlight their specific roles in developmental regulation and malignant transformation, suggesting their role as biological regulators and implicating their potential as therapeutic targets.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-094 - Identification of Oncofetal piRNAs in Lung (ID 9107)

      09:30 - 16:00  |  Author(s): K.W. Ng

      • Abstract
      • Slides

      Background:
      PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs (distinct from microRNAs) that recognize complementary DNA sequences in the nucleus. Their primary functions involve epigenetic control of gene transcription and maintenance of genomic stability through repression of mobile elements. Recent observations of cancer type specific aberrant expression have raised the possibility of a role for piRNAs in lung cancer. Here we characterize piRNA transcriptomes of fetal, adult and tumour lung tissue to identify fetal piRNA genes that are silenced in normal adult lung and re-activated in cancer. Our goal is to identify oncofetal piRNAs, which might represent ideal cancer therapeutic targets, as they are absent in normal adult lung tissue.

      Method:
      We determined piRNA expression profiles from small-RNA sequencing libraries using an in-house pipeline. All sequence reads were aligned to the hg38 build of the human genome. The expression levels of fetal lung samples (n=25) and two tumour/non-malignant paired cohorts (BCCA, n=118 and TCGA, n=91; derived from non-small cell lung cancer cases) were compared. piRNAs not expressed in non-malignant samples but with comparable expression in both fetal and tumour tissues were classified as oncofetal piRNAs. In order to identify the biological functions of the identified oncofetal piRNAs, we performed piRNA/DNA binding prediction using the miRanda algorithm adjusted for piRNA-specific features.

      Result:
      Our results provide a comprehensive characterization of piRNA expression in both normal and tumour lung tissues, as well as an unique piRNA expression profile of fetal lung tissues. A subset of the piRNA pool expressed in lung tissues are similarly expressed between fetal lung and lung tumours, but are absent in non-malignant tissue, implying that tumour initiation might involve the reactivation of developmental pathways. More importantly, target prediction analysis revealed that the identified oncofetal piRNAs are involved in key cellular processes, such as cell proliferation, migration and survival.

      Conclusion:
      Our study provides an unique and comprehensive characterization of the piRNA pool of lung tissues, as well as the identification of specific similarities in piRNA expression during both organ and tumour development. These similarities between fetal and tumour tissues might represent a promising avenue for the identification of strong biomarkers or optimal therapeutic targets with little toxicity for the treatment of lung cancer. Therefore, our study provides new and promising insights for lung tumour biology and may aid in the development of novel therapeutic approaches.

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