The comprehensive transcriptomic analysis regarding the mechanisms of PD-L1 expression and immune modulation in tumor microenvironment
종양미세환경 내 유전자 발현 분석을 통한 PD-L1 발현과 면역 회피 조절 기전 분석

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의과대학 의학과
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서울대학교 대학원
Tumor MicroenvironmentComprehensive analysisNext-generation sequencingTranscriptomeImmune evasionImmune checkpoint inhibitor
학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의학과, 2018. 2. 허대석.
Introduction: PD-L1 expression, existence of tumor-infiltrating lymphocyte (TIL), and mutational burden would be promising biomarkers to predict the efficacy of anti-PD-1/PD-L1 inhibitor, but clinical implication of these markers have not been completely established. In the current study, we analyze the immunogenomic properties in The Cancer Genome Atlas (TCGA) according to the classification of tumor based on PD-L1 expression and TIL. Moreover, upstream mechanism of PD-L1 expression and immune-suppressive signature of TIL were comprehensively analyzed.

Methods: The RNA expression levels of PD-L1 and CD8A in the samples in the pan-cancer database of TCGA (N=9,677) were analyzed. Based on their median values, the samples were classified into four tumor microenvironment immune types (TMITs). In tumor tissues of head and neck squamous cell carcinoma (HNSCC) of Seoul National University Hospital (SNUH cohort), PD-L1 expression and epithelial-mesenchymal transition (EMT) markers were assessed by immunohistochemistry and this finding was validated in 5 HNSCC cell lines.

Results: In TCGA analysis, the number of somatic mutations, PD-L1 amplification and oncogenic virus infection were significantly associated with TMIT I, respectively. Immune-suppressive signature by regulatory T-cells or M2 macrophage clearly affected survival among TME with highly infiltrated CD8-positive T-cells. PD-L1 expression was associated with EMT phenomenon, assessed by high vimentin and low E-cadherin expressions. Increased PD-L1 expression with EMT-positive was significantly associated with poor prognosis in SNUH cohort and TCGA cohort. PD-L1 expression was increased by cisplatin treatment in SNUH cohort and HNSCC cell lines, accompanying MAPK/ERK pathway.

Conclusions: This integrative analysis highlights the importance of the assessment of both PD-L1 expression and TIL signature in the era of immune checkpoint inhibitors.
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Theses (Ph.D. / Sc.D._의학과)
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