臺灣博碩士論文加值系統

台灣紫芝(Ganoderma formosanum)為台灣特有靈芝品種，在先前研究發現在液態深層醱酵培養法所生產的台灣紫芝胞外多醣體主要劃分PS-F2，具有免疫刺激及抗腫瘤的活性。在本研究中,我們探討經由UV突變且有較高多醣產量的菌株之免疫調節及抗腫瘤的特性。在預防及治療之動物模式裡，持續性給予小鼠口服PS-F2可以有效地抑制CT26腫瘤的生長及脾臟腫大的現象，且不會造成小鼠的健康有不良的影響。結果顯示，口服給予PS-F2可以促進脾臟內胞殺型T細胞及自然殺手細胞活化，且可以降低多型核髓原抑制細胞和調節型T細胞的比例。在腫瘤微環境中，口服給予PS-F2可以活化胞殺型T細胞和Th1細胞及減少腫瘤相關巨噬細胞的比例。在體外試驗中，PS-F2的刺激會促使單核型髓原抑制細胞表現成熟及分化的表面標記，並分泌發炎相關細胞激素TNF-α和 IL-6 。綜合以上結果，我們發現口服給予小鼠台灣紫芝胞外多醣PS-F2，可藉由活化體內的抗腫瘤免疫反應及減少脾臟和腫瘤內免疫抑制型細胞的累積,而達到減緩腫瘤生長的效果， 顯示PS-F2具有發展免疫治療藥劑的潛力。

Ganoderma formosanum is a native species of Ganoderma isolated in Taiwan, and our previous studies showed that a polysaccharide fraction, PS-F2, purified from the submerged culture fluid of G. formosanum ATCC 76538 exhibited immunostimulatory and antitumor property. In the current study, we investigated the immunomodulatory and antitumor effects of PS-F2 from a UV-mutated G. formosanum variant, which produced higher yields of PS-F2 than the original strain. In both preventive and therapeutic regimens, continuous oral administration of PS-F2 effectively suppressed the growth of colon 26 (CT-26) carcinoma and splenomegaly in tumor-bearing mice without adverse effects on the animals’ health. We found that PS-F2 treatment resulted in augmented cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses, while significantly reduced the accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and regulatory T (Treg) cells in the spleen. In the tumor, PS-F2 treatment markedly enhanced CTL and Th1 responses whereas reduced the accumulation of tumor-associated macrophages (TAMs). In vitro, PS-F2 treatment in bone-marrow derived monocytic-MDSC resulted in elevated levels of maturation and differentiation markers as well as the production of TNF-α and IL-6. Overall, our data demonstrated that oral treatment of PS-F2 from a UV-mutated G. formosanum variant in CT26 tumor-bearing mice activated antitumor immune responses and reduced the accumulation of immunosuppressive cells in the spleen and the tumor, leading to delayed tumor progression. PS-F2 has the potential to be developed as a cancer immunotherapeutic agent.

誌謝 I
中文摘要 II
Abstract III
Abbreviation IV
Contents VII
List of tables XVI
Chapter 1 Introduction 1
1.1 Ganoderma spp. (Lingzhi) 1
1.2 Immunostimulatory activity of Ganoderma polysaccharides 1
1.3 Cancer immunotherapy 2
1.4 Tumor microenvironment 2
1.4.1 Myeloid-derived suppressor cells (MDSCs) 3
1.4.2 Tumor-associated macrophages (TAMs) 4
1.4.3 Regulatory T cells (Tregs) 5
1.4.4 Regulatory B cells (Bregs) 6
1.4.5 Cancer-associated fibroblasts (CAFs) 7
1.4.6 Mesenchymal stem cells (MSCs) 7
1.5 Aims of this study 8
Chapter 2 Materials and Methods 9
2.1 Cell line and animal 9
2.2 Preparation of culture medium 9
2.2.1 PDB medium 9
2.2.2 ME-YE medium 9
2.3 Generate and purify PS-F2 from UV-mutated G. formosanum (NTU-1) 9
2.3.1 Generate the UV-mutated G. formosanum (NTU-1) from G. formosanum 9
2.3.2 Purification of PS-F2 from UV-mutated Ganoderma formosanum (NTU-1) 10
2.3.3 Measure total sugar content 11
2.4 To evaluate the immunstimulatory activities of PS-F2 from G. formosanum NTU-1 11
2.5 To determine antitumor effect of PS-F2 in CT26 tumor-bearing mice 11
2.5.1 To evaluate the dose-dependent antitumor effects of PS-F2 in CT26 tumor-bearing mice 11
2.5.2 To evaluate the antitumor activity of oral administration of PS-F2 in preventive and therapeutic models 11
2.5.3 Preparation of splenocytes from mouse spleens 12
2.5.4 Analyze cell population in spleens 13
2.5.5 Prepare single cell suspension from the tumor tissue 14
2.5.6 Analyze cell population in the tumor tissue 14
2.5.7 Intracellular staining 15
2.6 PS-F2 induced the differentiation of MDSC to APC in vitro 16
2.7 PS-F2 stimulated the production of TNF-α and IL-6 in BM-derived MDSCs 16
2.8 Statistical analysis 17
Chapter 3 Results 18
3.1 Production and characterization of the extracellular polysaccharides from G. formosanum NTU-1 18
3.2 PS-F2 produced by G. formosnum NTU-1 activated murine macrophages 19
3.3 Antitumor effect of different doses of PS-F2 produced by G. formosanum NTU-1 19
3.4 Antitumor effect of G. formosanum NTU-1 PS-F2 in CT26 tumor-bearing mice in the preventive model 20
3.4.1 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic effector Th1 cells in the preventive model 21
3.4.2 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic effector CTLs in the preventive model 22
3.4.3 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic MDSCs in the preventive model 22
3.4.4 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic regulatory T cells in the preventive model 23
3.4.5 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic NK cells in the preventive model 23
3.4.6 The effect of oral administration of G. formosanum NTU-1 PS-F2 on the MDSCs in the tumor tissue in the preventive model 24
3.4.7The effect of oral administration of G. formosanum NTU-1 PS-F2 on the tumor associated macrophage in the tumor tissue in the preventive model 24
3.4.8 The effect of oral administration of G. formosanum NTU-1 PS-F2 on effector Th1 cells in the tumor tissue in the preventive model 24
3.4.9 The effect of oral administration of G. formosanum NTU-1 PS-F2 on effector CTLs in the tumor tissue in the preventive model 25
3.5 Antitumor effect of G. formosanum NTU-1 PS-F2 in CT26 tumor-bearing mice in the therapeutic model 25
3.5.1 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic effector Th1 cells in the therapeutic model 26
3.5.2 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic effector CTLs in the therapeutic model 26
3.5.3 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic MDSCs in the therapeutic model 27
3.5.4 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic regulatory T cells in the therapeutic model 27
3.5.5 The effect of oral administration of G. formosanum NTU-1 PS-F2 on splenic NK cells in the therapeutic model 27
3.5.6 The effect of oral administration of G. formosanum NTU-1 PS-F2 on the MDSCs in tumor tissue in the therapeutic model 28
3.5.7 The effect of oral administration of G. formosanum NTU-1 PS-F2 on the tumor associated macrophages in the tumor tissue in the therapeutic model 28
3.5.8 The effect of oral administration of G. formosanum NTU-1 PS-F2 on effector Th1 cells in the tumor tissue in the therapeutic model 29
3.5.9 The effect of oral administration of G. formosanum NTU-1 PS-F2 on effector CTLs in the tumor tissue in the therapeutic model 29
3.5.10 The effect of oral administration of G. formosanum NTU-1 PS-F2 on regulatory T cells in the tumor tissue in the therapeutic model 30
3.6 G. formosanum NTU-1 PS-F2 induced differentiation and maturation of MDSC to APC in vitro 30
Chapter 4 Discussion 32
Tables and Figures 36
Reference 75

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