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研究生:黃景榮
研究生(外文):Jing-Rong Huang
論文名稱:新型醣酯直誘發免疫抗癌機轉之研究
論文名稱(外文):The mechanisms of superior anti-cancer efficacy of novel phenyl analogs of a-GalCer
指導教授:陳鈴津
指導教授(外文):Alice Ling-Tsing Yu
學位類別:博士
校院名稱:國立陽明大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:100
中文關鍵詞:醣酯質自然殺手T細胞免疫療法骨髓延生免疫抑制細胞
外文關鍵詞:glycolipidsNKT cellsimmunotherapyMDSC
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針對利用人體自身免疫力來治療癌症,其策略包括活化自身免疫系統或阻斷抑制免疫系統的分子。Alpha-GalCer,一種從海綿萃取出來的醣分子,可以用來活化自然殺手T細胞(NKT cells)來治療癌症。不幸的是,注射 -GalCer將會導致老鼠的NKT細胞產生長期的不反應,但其分子機制尚不清楚。在這裡,我們提出注射 -GalCer將觸發NKT細胞顯著的表現egr-2/3進而調控NKT細胞表現PD-1和CBL-B,從而導致NKT細胞的不反應。除此之外,我們還發現連續施打-GalCer會誘發產生免疫抑制的細胞,骨髓衍生抑制細胞myeloid-derived suppressor cells (MDSCs),進而減弱其抗腫瘤療效。我們進而發現 -GalCer所誘發的MDSCs其免疫抑制基因arg-1 mRNA表達增加了20倍,也增強PD1與PDL1的表達。此外-GalCer在肝臟NKT細胞所誘發的egr-2/3會進而去增加表現在NKT細胞表面的TRAIL和FasL的表現。而高度表現的TRAIL和FasL將會導致肝臟的損傷並誘發的危險信號分子,IL-33。我們也進而去証實大多數的IL-33是藉由肝臟的庫式細胞(kupffer cells)所分泌。最後我們進一步證實了IL-33確實會刺激巨噬細胞產生G-CSF,從而增加老鼠體內MDSCs的數目。因此,-GalCer誘導FasL/ TRAIL和IL-33對於-GalCer所誘導的肝毒性和MDSCs的積累提供了一種新機制。而與-GalCerr不同的是,其含苯基的類似物,phenyl-glycolipdis既不會誘導NKT產生不反
v
應也不增加MDSCs在體內的數目,並且,在小鼠中的腫瘤浸潤免疫細胞實驗下,連續注射phenyl-glycolipids 並不會像 -GalCer會增加腫瘤中MDSCs的數目。這些結果不僅對於 -GalCer誘發免疫抑制和誘導MDSCs的積累提出了一份新機轉,而且還提出機制來解釋phenyl-glycolipids其優越的抗腫瘤效力。我們的研究結果為NKT刺激醣脂作為疫苗佐劑和抗癌治療的發展具有重要意義。
Strategies for cancer immunotherapy include activating immune system for therapeutic benefit or blockade of immune checkpoints. To harness innate immunity to fight cancer, -GalCer has been used to activate NKT cells. Unfortunately, administration of -GalCer causes long term NKT-cell anergy, but the molecular mechanism is unclear. Here we showed that -GalCer triggered egr-2/3 which induced PD1 and Cbl-b in NKT-cells, leading to NKT-cell anergy. We also uncovered the induction of the immunosuppressive myeloid-derived suppressor cells (MDSCs) in the spleen by -GalCer which might attenuate its anti-tumor efficacy. The accumulation of MDSC was accompanied by 20-fold rise in their arg-1 mRNAs, and enhanced expression of PD1/PDL1. Furthermore, -GalCer- induced egr-2/3 in hepatic NKT-cells upregulated their TRAIL in addition to FasL, and induced alarm signaling molecule, IL-33 in Kupffer cells, presumably due to liver damage triggered by TRAIL/FasL. We further demonstrated that IL-33 stimulated macrophages to produce G-CSF, which in turn, boosted MDSCs. Thus, -GalCer-induced FasL/TRAIL and IL-33 provided a novel mechanism underlying -GalCer induced hepatotoxicity and MDSC accumulation. In contrast, analogs of -GalCer containing phenyl group in the lipid tail could neither induced NKT anergy
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nor enhanced MDSCs accumulation, Furthermore, tumor-infiltrating MDSCs in mice injected repeatedly with -GalCer were 2-fold higher than those treated with phenyl-glycolipids. These results not only reveal the induction of MDSC via IL-33 as a new mechanism for -GalCer-elicited immunosuppression but also provided one of the mechanisms underlying the superior anti-tumor potency of phenyl-glycolipids. Our findings have important implications for the development of NKT-stimulatory glycolipids as vaccine adjuvants and anti-cancer therapeutics.
Signature i
Thesis approvel ii
誌謝 iii
中文摘要 iv
Abstract vi
Contents viii
List of Figures x
List of table xii
Chapter I: Introduction 1
1.1: Cancer Immunotherapy and NKT cells: 1
(1) Passive immunotherapy 1
(2) Active Immunotherapy 2
(A) Cytokines 2
(B) Cancer Vaccine 3
(C) Cell-based therapy 4
Adoptive T-cell therapy 4
Dendritic cell therapy 5
NK cell therapy 6
(3) Immune checkpoint blockade 7
(4) NKT cells therapy 9
1.2: Molecular mechanism of T/NKT cell anergy 10
1.3: Myeloid derived-suppressor cells in cancer 11
1.4: IL-33 in immune and cancer 13
Chapter II : Materials and Methods 15
2.1: Mice and cell lines 15
2.2: Reagents and Flow cytometry 15
2.3: Measurement of in vivo responses of glycolipids and determination of TC-1 lung metastasis 17
2.4: MDSCs, NKT cells enrichment, liver MNC, and kupffer cells isolation 17
2.5: RNA isolation and Reai-time PCR 19
2.6: Determination of tumor infiltrating lymphocyte 20
2.7: Neutralization of IL33 receptor ST2 21
2.8: Statistical analysis 21
Chapter III: Results 22
3.1: Potent immune-modulating and anti-cancer effects of NKT cell stimulatory glycolipids 22
3.2: Repeated administration of phenyl analogs of -GalCer did not induce NKT cell anergy 23
3.3: Failure of phenyl-glycolipid to induce NKT anergy was not due to stimulation of different subsets of NKT cells 24
3.4: Upregulation of egr-2/3 was associated with -GalCer induced NKT cell anergy 25
3.5: Repeated administration of -GalCer but not phenyl-glycolipids dampened its anti-tumor efficacy by active immunosuppression which is independent of T-reg cells 27
3.6: Accumulation of splenic MDSCs with enhanced expression of arg-1, inos, PD1 and PDL1 in response to -GalCer but not phenyl-glycolipids, which was iNKT-dependent 30
3.7: IL-33 in response to NKT-mediated liver damage can induce G-CSF secretion from macrophages to cause MDSCs accumulation 32
Chapter IV : Discussion 36
Chapter V : Reference 43
Abbrevation 99


List of Figures
Figure 1: The structure of synthetic glycolipids 58
Figure 2: The Th1/Th2 cytokine ratio in human NKT cells induced by 16 glycolipids analogs 59
Figure 3: Expansion of mouse splenocytes upon administration of -GalCer and its analogs 60
Figure 4: Anti-cancer efficacy of C1 and its analogs in lung cancer bearing mice 61
Figure 5: Serum Th1/Th2 cytokine profiles induced by repeated administration of -GalCer and phenyl analogs in C57BL/6 mice 62
Figure 6: The sub-population profiles of the mouse spleen upon repeated administration of -GalCer and phenyl analogs 63
Figure 7: Serum Th1/Th2 cytokine profiles upon repeated administration of -GalCer and phenyl analogs in J18-/- mice 64
Figure 8: Usage of the NKT V receptors in mouse splenocytes upon stimulation by various glycolipids 65
Figure 9: The effect of glycolipids on PD1 expression in splenic NKT cells 66
Figure 10: Effect of glycolipids on the expression of cbl-b in splenic CD1d-restricted NKT cells 67
Figure 11: Kinetics of IFN- induction by repeated injection of OCH 68
Figure 12: Effect of glycolipids on the expression of egr-2/3 in the splenic NKT cells 69
Figure 13: Comparison of anti-cancer efficacy between single and multiple doses of C1 70
Figure 14: Comparison of anti-cancer efficacy between single and multiple doses of phenyl-glycolipids 71
Figure 15: Th1/Th2 ratio (IFN-/IL-4) in mouse sera after treatment with various glycolipids 72
Figure 16: Effects of various glycolipids on the proliferation of mouse splenocytes in response to anti-CD3/28 73
Figure 17: Effects of single or repeated injection of various glycolipids on induction of TGF- 74
Figure 18: Effect of single or repeated injection of various glycolipids on T-reg cells in mouse spleen 75
Figure 19: Effect of various glycolipids on the proliferation of mouse CD90.2+ cells upon stimulated with anti-CD3/28 76
Figure 20: Effect of -GalCer and phenyl analogs on serum IL-10 and IL-13 cytokine secretion 77
Figure 21: Effect of single or repeated injection of various glycolipids on the number of splenic MDSCs 78
Figure 22: Inhibition of lymphocyte proliferation by MDSCs isolated from mice treated with various glycolipids 79
Figure 23: Effect of repeated injection of various glycolipids on the number of tumor infiltrating MDSCs in mice bearing with TC-1 tumor 80
Figure 24: Effect of various glycolipids on the expression of PD1 and PDL1 in splenic MDSCs 81
Figure 25: Effect of various glycolipids on the expression of arg-1 and inos in splenic MDSCs of C57BL/6 mice 82
Figure 26: Effect of various glycolipids on the expression of arg-1 and inos in splenic MDSCs of CD1d-/- and J18-/- mice 83
Figure 27: The photographs of C57BL/6 mouse spleens captured at day 3 and 7 after injection of the indicated glycolipids. 84
Figure 28: Effect of various glycolipids on IL-33 expression in mouse liver 85
Figure 29: Effect of various glycolipids on IL-33 expression in mouse spleen 86
Figure 30: Determination of IL-33 expression in the isolated sub-population of liver cells 87
Figure 31: Effect of various glycolipids on IL-33 expression in J18-/- mouse liver 88
Figure 32: Effect of various glycolipds on the expression of FasL/TRAIL in the liver NKT cells 89
Figure 33: Effect of anti-ST2 Abs on MDSCs accumulation after treatment of mice with C1 90
Figure 34: The time kinetics of G-CSF induction upon repeated administration of -GalCer and phenyl analogs in C57BL/6 mice 91
Figure 35: Effect of anti-ST2 Abs on the G-CSF induction in the mouse sera after treatment of mice with C1 92
Figure 36: The photographs of C57BL/6 (n=3) mouse spleens captured at day 7 after injection of C1 ± anti-ST2 or isotype control Abs 93
Figure 37: Effect of anti-ST2 Abs on the expression of PD1 on splenic NKT cells after treatment of mice with C1 94
Figure 38: Effect of IL-33 on the expression of G-CSF in Raw264.7 cells 95
Figure 39. A proposed model for glycolipids induced accumulation of MDSCs mediated by NKT 96

List of table
Table 1: Cancer Immunotherapy Monoclonal Antibodies 97


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