- 學位論文
解碼驅動自然殺手細胞衰竭軌跡之分子機制
Deciphering the Molecular Mechanism Driving Natural Killer (NK) Cell Exhaustion Trajectory
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摘要
自然殺手 (NK) 細胞在針對腫瘤的先天免疫反應中發揮至關重要的作用。長時間暴露於多重刺激會損害其效用功能 (effector functions) ，包括降低其對腫瘤細胞或病毒感染細胞的細胞毒性 (cytotoxicity) 並阻礙增生能力 (proliferation)，最終導致 NK 衰竭 (exhaustion)。 儘管如此，由於NK 細胞群有一定的異質性 (heterogeneity)，了解其潛在機制並準確定義NK 細胞衰竭表現型 (phenotype) 仍然是一個挑戰, 因為它不像CD8+ T 細胞般能直接利用T 細胞受體 (TCR) 作譜系追蹤 (lineage tracing)，這使得無法像對 T 細胞一樣精確追蹤 NK 細胞的衰竭過程 。因此，本研究旨在透過剖析 NK 細胞衰竭的複雜軌跡，並尋找能夠改善目前 NK用於癌症治療細胞移植的產品。 通過利用單細胞RNA測序（scRNA-seq）數據並重新應用CytoTRACE（Gulati et al，2020）來研究免疫細胞的衰竭 狀態，我成功重建了自然殺手細胞（NK）衰竭的軌跡，並解析了其進程中的轉錄變化。 這項研究揭示了腫瘤微環境中 NK 細胞衰竭的先前未被探索的機制，並識別出多個癌症資料集中的不同 DEGs 及其富集途徑。這項研究的主要發現包括與細胞毒性相關的 DEGs（例如 NKG7）、核糖體蛋白的意外角色（例如 RPS3），以及與肌動蛋白細胞骨架相關的基因（例如 PFN1、ARPC2），這些基因可能促進 NK 細胞衰竭期間的功能障礙。此外，六個轉錄因子，包括 HMGB1 和 PCBP1，被識別為可能調控 NK 細胞衰竭的因子，這些發現提供了新的見解及治療靶點，對於解決癌症中的免疫功能異常具有潛在意義。
並列摘要
Natural killer (NK) cells play a crucial role in the innate immune response against tumors. Prolonged exposure to multiple stimulants however would compromise their effector functions, ie. impaired their cytotoxic function and hampered anti-tumor capabilities, eventually leading to a state called NK exhaustion. Still, understanding and defining NK cell exhaustion is challenging due to the heterogeneity of NK cells. In contrast to the well-characterized CD8+ T cells, which benefit from T cell receptor (TCR) lineage tracing, the lack of a similar mechanism in NK cells has hindered the ability to track their exhaustion progression. Therefore, this study aims to address this gap by dissecting the intricate trajectory of NK cell exhaustion and exploring potential strategies for enhancing current NK adoptive therapeutic products for cancer treatments. By utilizing single-cell RNA sequencing (scRNA-seq) data and repurposing CytoTRACE (Gulati et.al, 2020) for studying immune cell exhaustion, I was able to reconstruct NK exhaustion trajectory and dissect the transcriptional changes during its progression. This study reveals previously unexamined mechanisms of NK cell exhaustion within the tumor microenvironment, identifying distinct sets of DEGs and their enriched pathways across multiple cancer datasets. Key findings include DEGs linked to cytotoxicity (e.g., NKG7), unexpected roles of ribosomal proteins (e.g., RPS3), and actin cytoskeleton-related genes (e.g., PFN1, ARPC2), which may contribute to NK dysfunction during exhaustion. Additionally, six transcription factors, including HMGB1 and PCBP1, were identified as potential regulators of NK exhaustion, providing new insights and therapeutic targets for addressing immune dysfunction in cancer.
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