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研究生：	楊佩姍 Yang, Pei-Shan
論文名稱：	T細胞中Rab37以胞吐作用調控chitinase 3-like 1蛋白分泌進而促使肺癌進程 Rab37 mediates exocytosis of chitinase 3-like 1 in T cells to promote lung cancer progression
指導教授：	王憶卿 Wang, Yi-Ching
學位類別：	碩士 Master
系所名稱：	醫學院 - 藥理學研究所 Department of Pharmacology
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	83
中文關鍵詞：	肺癌、Rab37 、CHI3L1 、胞吐作用、中和抗體、抗腫瘤小鼠模式
外文關鍵詞：	Lung cancer, Rab37, CHI3L1, exocytosis, neutralizing antibody, anti-tumor allograft model
相關次數：	點閱：64 下載：0
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研究背景: 許多證據顯示Rab small GTPase調控胞吐作用 (exocytosis) 的異常參與癌化過程。本研究室未發表數據顯示全身性Rab37基因剔除 (knockout) 小鼠與野生 (wild-type) 小鼠的脾臟CD8 T細胞培養液 (conditioned media)，以細胞激素以及趨化激素晶片 (cytokines/ chemokines array) 分析發現，chitinase 3-like 1 (CHI3L1, 類幾丁質3) 的分泌量與Rab37的表現量具有關聯性。T細胞中的CHI3L1已被揭露能誘導黑素瘤的肺部轉移；然而，T細胞中CHI3L1的運輸模式從未被探究過。
研究目的: 本研究旨在鑒定T細胞是否以Rab37調控CHI3L1的胞吐作用以促進肺癌進展，並研究針對以Rab37 / CHI3L1為主軸的治療價值性。
研究結果: 我們的ELISA結果證實，與Rab37野生小鼠組相比，在Rab37剔除小鼠組的脾臟中CD4和CD8 T細胞的CHI3L1分泌量都降低。為了研究Rab37是否參與CHI3L1的胞吐作用，我們檢測了過度表現Rab37野生型、與GTP結合的活化態Q89L和與GDP結合的非活化態T43N的Jurkat T細胞培養液中CHI3L1的含量，結果顯示，這些由Jurkat T細胞收集的培養液證實Rab37以GTPase活性模式調控CHI3L1的分泌，此結果也透過胞內Rab37專一性囊泡的分離法和全反射倒立螢光顯像進一步被證實；此外，我們透過共軛焦顯微鏡在Jurkat T細胞和體外培養的脾臟CD8 T細胞以及活體內浸潤到肺癌腫瘤的T細胞中，發現Rab37和CHI3L1的共定位現象 (colocalization)。再者，我們發現血漿 (plasma) 中CHI3L1含量高的肺癌病患具有較低生存率的關聯性。為了探討CHI3L1是否適合作為治療性靶標，我們開發了中和CHI3L1的抗體藥物，我們證實了中和CHI3L1的抗體藥物抑制了肺癌細胞中AKT的活化；重要的是，在肺癌同種移植的小鼠模式中，我們更進一步驗證了這個抗體在沒有血清生化與器官毒性的情況下減緩了腫瘤生長。
研究結論：本研究首次證明T細胞中Rab37調控CHI3L1的分泌，並且抑制Rab37 / CHI3L1軸線的促腫瘤功能具有治療的重要性。

Background: Accumulating evidence indicates implication of Rab small GTPase-mediated exocytosis in tumorigenesis. We have established whole body Rab37 knockout (KO) mice model. The cytokine/chemokine profiles of conditioned media (CM) derived from wild-type (WT) or Rab37 KO mice revealed that the secreted level of chitinase 3-like 1 (CHI3L1) correlated with Rab37 expression in splenic CD8+ T cells. CHI3L1 in T cells has been shown to induce melanoma lung metastasis. However, the trafficking mode of CHI3L1 in T cells has never been studied.
Purpose: This study aims to determine whether Rab37-mediated exocytosis of CHI3L1 in T cells plays a promoting role in lung cancer progression and to investigate the treatment value of targeting Rab37/CHI3L1 axis.
Results: Our ELISA results confirmed that secreted level of CHI3L1 decreased in both splenic CD4+ and CD8+ T cells from Rab37 KO mice compared to WT mice group. To investigate whether Rab37 was involved in CHI3L1 exocytosis, we examined the presence of CHI3L1 in the CM from Rab37 wild-type, constitutive active GTP-bound Q89L and dominant negative GDP-bound T43N overexpressing Jurkat T cell lines. Notably, the collected CM from Jurkat T cell lines manipulated for Rab37 showed the secretion of CHI3L1 via Rab37 in a GTPase-dependent manner, which was further confirmed by Rab37-specific vesicle isolation and total internal reflection fluorescence images. In addition, we revealed the colocalization of Rab37 and CHI3L1 in Jurkat T cell line and ex vivo cultured splenic CD8+ T cells as well as in vivo infiltrated T cells from syngeneic orthotopic Lewis lung carcinoma (LLC) tumors by confocal microscopy. Furthermore, we found that higher CHI3L1 concentration in the plasma associated with poor survival in lung cancer patients. To validate CHI3L1 as a therapeutic target, we developed an anti-CHI3L1 neutralized antibody. We demonstrated that neutralized CHI3L1 antibody inhibited AKT activation in the lung cancer cells. Importantly, we further confirmed that this antibody suppressed the tumor growth in the mice implanted with LLC allografts without serum biochemical and organ toxicity.
Conclusion: These results provide first evidence that Rab37 mediates CHI3L1 secretion in T cells and tumor promoting function of Rab37/CHI3L1 axis in T cells may possess the therapeutic implications.

CONTENTS
Introduction	1
I.	Lung cancer 	1
(a)	Epidemiology of lung cancer	1
(b)	Therapeutic strategies in lung cancer	1
II.	Tumor immune microenvironment 	3
(a)	Role of immune cells in tumor microenvironment	3
(b)	Role of chitinase 3-like 1 in tumor microenvironment	4
III.	Chitinase 3-like 1 (CHI3L1) signaling in promoting tumorigenesis	5
(a)	CHI3L1 receptor on cancer cells	5
(b)	CHI3L1 signaling in cancer cells	6
(c)	CHI3L1 expression in tumor microenvironmental cells	6
IV.	Rab GTPases in vesicle trafficking	7
(a)	Oncogenic Rab GTPases	7
(b)	Tumor suppressor Rab GTPases	8
(c)	Role of Rab37 mediated-exocytosis in tumor progression	9
Study basis and specific aims	11
Materials and methods	13
I.	Animal studies	13
II.	Cell lines, splenic T cell isolation and culture condition	14
III.	Plasmid, RNAi and transfection	16
IV.	Cytokine and chemokine array	16
V.	Vesicle isolation and immunoprecipitation	17
VI.	Enzyme-linked immunosorbent assay	17
VII.	Conditioned media collection	18
VIII.	Western blot analysis	18
IX.	Confocal microscopy	19
X.	Total internal reflection fluorescence microscopy	19
XI.	Immunohistochemistry assay (IHC) and immunofluorescence-IHC	20
XII.	Flow cytometry	21
XIII.	RNA extraction and quantitative reverse transcriptase polymerase   chain reaction assay	22
XIV.	Patient recruitment and analyses	23
XV.	Statistical analysis	23
Results	24
I.	Rab37-mediated exocytosis promoted CHI3L1 secretion in T cells	25
(a)	Cytokine and chemokine array of splenic T cells from Rab37 wild-type and knockout mice identified cargo candidates of Rab37	25
(b)	CHI3L1 was a cargo of Rab37-mediated exocytosis in T cells   regulated in a GTP-dependent manner	26
(c)	Rab37-mediated CHI3L1 secretion induced AKT phosphorylation      in cancer cells	28
II.	CHI3L1-neutralizing antibody treatment improved the therapeutic efficacy to inhibit tumor growth	29
(a)	CHI3L1-neutralizing antibody treatment inhibited AKT phosphorylation     in cancer cells in vitro	29
(b)	CHI3L1-neutralizing antibody treatment inhibited tumor growth       in subcutaneous model in vivo	30
(c)	CHI3L1-neutralizing antibody treatment inhibited tumor growth       and tumor metastases in orthotopic model in vivo	31
(d)	Rab37 protein expression positively correlated with CHI3L1 level      in LLC allograft tumor specimens in vivo	32
III.	High CHI3L1 expression in plasma samples or tumor specimens predicted poor prognosis of lung cancer patients	33
(a)	High plasma CHI3L1 level predicted poor prognosis of lung cancer patients	33
(b)	Concordantly high expression of Rab37 and CHI3L1 in T cells of   tumor specimens 	34
Discussion	35
References	39
Tables	48
Figures	55
Appendix Figures and Table	76
 
TABLE CONTENTS
Table 1.	The plasmids and their characteristics used                in the current study	49
Table 2.	The antibodies and their reaction conditions used           in the current study	50
Table 3.	The primers used in the current study	52
Table 4.	Alteration of CHI3L1 protein expression in relation         to clinicopathological parameters in 161 lung cancer         patients’ plasma samples	53
Table 5.	Cox regression analysis of risk factors for       cancer-related death in lung cancer patients	54
 
FIGURE CONTENTS
Figure 1.	Cytokine/chemokine array identified CHI3L1 as          a cargo candidate of Rab37 in T cells	56
Figure 2.	Rab37 knockout mice derived T cells reduced CHI3L1 secretion	57
Figure 3.	Identification and validation of CHI3L1 cargo secretion      in Rab37-specific vesicles and conditioned media	58
Figure 4.	Rab37 mediated CHI3L1 trafficking and exocytosis in       T cells in a GTP-dependent manner	60
Figure 5.	Examination of the binding affinity and function of recombinant CHI3L1 (rCHI3L1) protein in H1299 cells	62
Figure 6.	Blockade of CHI3L1 using neutralizing CHI3L1    antibody attenuated the effect of rCHI3L1 protein        on H1299 cells	64
Figure 7.	CHI3L1-neutralizing antibody treatment inhibited     tumor growth in subcutaneous model in vivo	66
Figure 8.	CHI3L1-neutralizing antibody treatment inhibited     tumor growth in orthotopic model in vivo	69
Figure 9.	Plasma CHI3L1 level served as a prognosis biomarker     of lung cancer patients	72

Figure 10.	Correlation between Rab37 and CHI3L1 expression       in lung cancer patients	73
Figure 11.	The schematic model of Rab37 / CHI3L1 axis in infiltrated   T cells in regulation of tumor growth of lung cancer	75
 
APPENDIX CONTENTS
Appendix Figure 1.	How tumor genotypes and phenotypes shape        the tumor immune microenvironment	77
Appendix Figure 2.	Binding of CHI3L1 and IL-13Rα2	78
Appendix Figure 3.	The CHI3L1 / CD44-IL-13Rα2 signaling pathway	79
Appendix Figure 4.	Activation of CHI3L1 signaling in cancer  development	80
Appendix Figure 5.	CHI3L1 drives an immunosuppressive and growth promoting microenvironment	81
Appendix Figure 6.	Schematic diagram of Rab GTPase cycle	82
Appendix Table 1.	CHI3L1 expression in lung cancer patient-derived samples reported in the literature	83
                                    

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