白血病抑制因子調控口腔癌巨噬細胞免疫反應

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隋昀華(Yun-Hua Sui) 查詢紙本館藏

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生醫科學與工程學系

論文名稱

白血病抑制因子調控口腔癌巨噬細胞免疫反應
(Leukemia inhibitory factor regulates macrophage immune response in oral squamous cell carcinoma)

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摘要(中)

口腔鱗狀上皮細胞癌(口腔癌)的高復發率與免疫抑制的微環境有密切相關。巨噬細胞在免疫微環境調控中扮演重要角色。白血病抑制因子為多效性的細胞激素且和多種癌惡化相關。其中白血病抑制因子是否會調控巨噬細胞且進一步重塑腫瘤微環境仍有許多未知。本研究目的為釐清白血病抑制因子在口腔癌中調控腫瘤相關巨噬細胞扮演的角色以及探討白血病抑制因子與巨噬細胞調控免疫反應的臨床意義。分析 TCGA 口腔癌資料庫顯示口腔癌患者表現較高白血病抑制因子與 M2 巨噬細胞標誌(CD206、 CD163 和 VEGF)。癌組織中較高白血病抑制因子的表現量與較差的整體存活率相關 (p =0.0019)。高免疫細胞白血病抑制因子表現的口腔癌切片中巨噬細胞傾向聚集在腫瘤邊緣，免疫細胞白血病抑制因子表現量低或陰性的樣本中，型態較大的巨噬細胞偏向聚集於腫瘤核心。細胞實驗顯示白血病抑制因子可促使巨噬細胞分化為免疫抑制型態，由較低 M1 型標誌(iNOS、CD86)和增加 M2 型態標誌(CD163、CD209)表現得知。將巨噬細胞和癌細胞共同培養時，白血病抑制因子可促進癌細胞生長與爬行且降低巨噬細胞對癌細胞的毒殺能力。可溶性白血病抑制因子受體為白血病抑制因子的拮抗劑。在培養環境中加入可溶性白血病抑制因子受體會降低白血病抑制因子所促使的免疫抑制反應。單細胞轉錄體分析顯示白血病抑制因子降低巨噬細胞抗原呈現功能的基因表現，與定量即時逆轉錄聚合酶連鎖反應結果一致。轉錄體功能性分析顯示白血病抑制因子促使巨噬細胞中第一型干擾素、TNFR 以及 Hippo-YAP 相關信號途徑的分子被抑制。此外，白血病抑制因子可能是透過活化 YAP1 誘導巨噬細胞 M2 相似型態趨化，可由較多YAP1入核以及增加的活化YAP1和YAP1下游蛋白CTGF、IGFBP3 和 PDGFR⍺β 表現量得知。以藥物阻斷 YAP1 信號傳導可抑制白血病抑制因子所調控的巨噬細胞免疫反應。本研究結果顯示白血病抑制因子在口腔癌巨噬細胞中會透過活化 YAP1，促進免疫抑制的腫瘤微環境形成。藉由抑制白血病抑制因子對巨噬細胞的調控，如可溶性白血病抑制因子受體及YAP1抑制劑的應用，有潛能在高白血病抑制因子表現的患者中反轉其免疫抑制性的微環境。

摘要(英)

The high incidence of local recurrence in oral squamous cell carcinoma (OSCC) is linked to an immunosuppressive microenvironment. Macrophages play a pivotal role in remodeling tumor immunity. Leukemia inhibitory factor (LIF) is a pleiotropic cytokine with functions associated with tumor progression. Nevertheless, whether LIF modulates the functions of macrophages and hence induces a tumor-promoting microenvironment remains to be explored. In this study, we aimed to investigate the role of LIF in regulating function of macrophages and to determine the clinical relevance between LIF and macrophage-mediated immunity within OSCC. By analyzing the TCGA-OSCC database, we found higher levels of LIF and M2-like macrophage markers (CD206, CD163, VEGF) in tumor samples compared to normal counterparts. An elevated LIF expression was further correlated with a poorer overall survival (p =0.0019). Immunohistological analysis on OSCC revealed that macrophages were predominantly localized at the periphery of tumors infiltrated with LIF-rich immune cells. On the other hand, macrophages with a larger phenotype were found in the core area of tumors, in which the LIF immunoreactivities were negative to weak in immune populations. Treatment of recombinant LIF (rLIF) induced an immunosuppressive polarization, which was supported by increased expression of M2-like markers (CD163 and CD209) and decreased levels of M1-like markers (iNOS and CD86). In a macrophage-cancer cell coculture system, rLIF treatment promoted the motility and proliferation of OSCC cells, whereas decreased cytotoxic abilities of macrophages. Treating macrophages with soluble LIF receptor (sLIFR), a LIF antagonist, partly reversed the rLIF-mediated M2-like polarization and decreased cancer cytotoxicity. Results of single-cell RNA sequencing on rLIF-treated OSCC biopsy revealed suppression of antigen presentation process in macrophages, which was further verified by quantitative real-time polymerase chain reaction. Further, rLIF treatment in macrophages resulted in suppressed functions on type I interferon production, TNFR, and Hippo-YAP signalings. Mechanistically, rLIF-induced M2- like polarization may be promoted through YAP1 activation, which was evident by an enhanced YAP1 nuclear translocation and increased expressions of active YAP1 and its downstream proteins (CTGF, IGFBP3, and PDGFR⍺β). Pharmaceutical inhibition of YAP1 reduced the rLIF-mediated immune responses in macrophages. Collectively, our findings shed light on the LIF-mediated effects on macrophages. We proposed that LIF assists in establishing an immune- suppressive and tumor-promoting microenvironment through activating YAP1 in OSCC. Blockade of LIF-mediated effects might have the potential of converting the immunosuppressive microenvironment for selected OSCC patients.

關鍵字(中)

★ 白血病抑制因子
★ 口腔鱗狀上皮細胞癌
★ 巨噬細胞

關鍵字(英)

★ LIF
★ OSCC
★ Macrophage

論文目次

Chinese Abstract...................................................................................................ii English Abstract...................................................................................................iii Table of Contents................................................................................................. iv List of Figures.....................................................................................................vii List of Tables ....................................................................................................... ix List of Abbreviations ............................................................................................ x Chapter I Introduction......................................................................................... 1
1-1 Head and neck squamous cell carcinoma ................................................................... 1 1-1-1 Oral squamous cell carcinoma....................................................................... 1 1-1-1-1 Human papillomavirus positive OSCC ...................................................... 2
1-2 Leukemia inhibitory factor ......................................................................................... 3 1-2-1 Leukemia inhibitory factor in solid tumors ................................................... 4
1-3 Tumor microenvironment........................................................................................... 4 1-3-1 Tumor-associated macrophages..................................................................... 6 1-3-2 Tumor-associated macrophages in OSCC TME............................................ 7
1-4 Yes-associated Protein 1............................................................................................. 7 1-4-1 Role of YAP1 in macrophages ...................................................................... 8
Chapter II Materials and Methods ...................................................................... 9
2-1 Cell culture ................................................................................................................. 9 2-2 PBMC isolation from whole blood samples............................................................... 9 2-3 Macrophage differentiation ........................................................................................ 9 2-4 Real-time quantitative polymerase chain reaction (QRT-PCR)............................... 10
iv
2-5 Bulk RNA sequencing and library construction....................................................... 10 2-6 Single-cell sample preparation and library construction .......................................... 11 2-7 RNA sequencing data analysis ................................................................................. 11 2-8 Immunohistochemistry (IHC) .................................................................................. 11 2-9 Immunocytochemistry (ICC).................................................................................... 12 2-10 Western blot............................................................................................................ 13 2-11 Live cell time-lapse imaging .................................................................................. 13 2-12 Macrophage-cancer killing assay ........................................................................... 14 2-13 EdU (5-Ethynyl-2-deoxyuridine) cell proliferation assay ...................................... 14 2-14 Statistics.................................................................................................................. 15
Chapter III Results ............................................................................................ 16
3-1 High expression of LIF is identified in OSCC TME................................................ 16 3-2 Single cell analysis of TAMs under in vitro LIF stimulation................................... 16 3-3 LIF regulates MHC class II molecules in macrophages........................................... 17 3-4 LIF alters macrophage polarization.......................................................................... 18 3-5 LIF-treated macrophages exhibit lowered cytotoxicity towards OSCC................... 18 3-6 MDMs display dysfunctional immune regulation under LIF stimulation................ 19
3-6-1 Positive correlation between LIF and YAP1 signaling molecules in HNSCC ............................................................................................................ 20
3-7 LIF promotes YAP1 activation in TAMs................................................................. 20 3-8 Inhibition of YAP1 decreases LIF-mediated effects in TAMs ................................ 21 3-9 LIF regulates antigen presentation pathway in OSCC ............................................. 21
v

Chapter IV Conclusions and Discussions .................................................. 22 Chapter V Figures and Tables .......................................................................... 24 References........................................................................................................... 56

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指導教授

劉淑貞(Shu-Chen Liu)

審核日期

2023-8-16

推文