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系統識別號 U0026-0507201520242000
論文名稱(中文) 分析瀰漫性大型B細胞淋巴癌病人的T細胞反應與相關之臨床及病理特徵
論文名稱(英文) Analysis of host T-cell response in diffuse large B-cell lymphoma (DLBCL) and correlation with clinicopathological features
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所碩士在職專班
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 張珍
研究生(英文) Chen Chang
電子信箱 cornea100@hotmail.com
學號 S97001116
學位類別 碩士
語文別 英文
論文頁數 63頁
口試委員 召集委員-蘇益仁
口試委員-謝奇璋
口試委員-陳彩雲
指導教授-張孔昭
中文關鍵字 瀰漫性大型B細胞淋巴癌  抗腫瘤免疫  周邊血液  流式細胞儀  調節型T細胞  原發性中樞神經系統  預後 
英文關鍵字 diffuse large B-cell lymphoma  antitumor immunity  peripheral blood  flow cytometry  regulatory T cells  primary central nervous system  prognosis 
學科別分類
中文摘要 中文摘要

一、源起

免疫系統在清除癌症細胞扮演著重要角色,而癌症免疫反應為一複雜機轉,有潛在可能作為治療標的。在傳統的理論模式中,腫瘤抗原會被樹突細胞捕獲處理並被呈現給作用型/記憶型T細胞及細胞毒性型T細胞,這些細胞會接著辨識出並攻擊腫瘤細胞;然而調節型T細胞會抑制其他免疫細胞以減少組織破壞。不像實質腫瘤,淋巴癌從免疫系統衍生而來,可能直接影響宿主免疫系統並產生較難預測的結果。瀰漫性大型B細胞淋巴癌(DLBCL)是一種病程進展快速的B細胞淋巴癌,為成人最常見的淋巴癌種類。分析宿主免疫細胞可能在評估預後及臨床處置上,提供有用的資訊。此外,免疫監視功能不佳被預期會影響腫瘤發展,而在人類,腦是一個免疫除役的環境,可能導致宿主抗腫瘤免疫反應不佳。因此我們針對另一特殊亞分類-中樞神經系統瀰漫性大型B細胞淋巴癌(PCNSL)並與周邊相對應的淋巴癌作比較。

二、方法

以流式細胞儀免疫表型分類法,分析共77位瀰漫性大型B細胞淋巴癌(DLBCL)的病人及30位健康志願者的周邊血樣本。偵測全血細胞計數,各種T細胞分類及樹突細胞,並與臨床病理特徵做比對。此外,我們另從32個中樞神經系統瀰漫性大型B細胞淋巴癌(PCNSL)切片標本及30個免疫健全病人取得之低分期、非中樞神經系統的瀰漫性大型B細胞淋巴癌(DLBCL)的標本做研究;藉由組織免疫化學染色方式,分析並評估免疫細胞密度及分布,包括樹突細胞(DC-LAMP+及S100+),作用型/記憶型T細胞 (CD45RO+),細胞毒性型T細胞(granzyme B+)以及腫瘤表現人類抗原HLA-DR的情況。

三、結果

與健康志願者比較,瀰漫性大型B細胞淋巴癌(DLBCL)病人有顯著較高白血球、單核球計數(P<0.001);較高比例(%)的中性球(P<0.001),自然性調節型T細胞(Tregs, CD3+Foxp3+, P<0.001),不成熟樹突細胞(CD83−CD1a+, P=0.005);及較低比例的淋巴球(P<0.001)和幫助型T細胞(P=0.038)。在單變項分析中,高中性球計數、誘發性調節型T細胞,連同高國際預後指數(IPI)分數,及其他高風險臨床指標,為存活不佳因子;在多變項分析中,高調節型T細胞仍具顯著意義。淋巴球抑制與不良的臨床因子有相關聯性、高自然性調節型T細胞與低CD4+/CD8+比值(P=0.035)、較多未成熟樹突細胞(P=0.055)相關聯。在中樞神經系統瀰漫性大型B細胞淋巴癌(PCNSL),病人總存活率較差,比較中樞神經系統瀰漫性大型B細胞淋巴癌(PCNSL)與周邊瀰漫性大型B細胞淋巴癌切片標本,前者在背景中有較少的細胞毒性型細胞,為一不良預後因子(P=0.004)。在腫瘤中S100+細胞浸潤與T細胞浸潤和圍繞情形有正向相關聯性。

四、結論

在瀰漫性大型B細胞淋巴癌(DLBCL)病人的血液中,免疫細胞有所改變;研究結果亦支持調節型T細胞在適應性免疫系統扮演抑制的角色並與不良危險預後因子相關聯。相比於非中樞神經系統瀰漫性大型B細胞淋巴癌,在此位置原發者(PCNSL)的基礎抗腫瘤免疫反應較為不足。此結果可能在中樞神經系統瀰漫性大型B細胞淋巴癌(PCNSL)預後不佳中占有一席之地;輔助型樹突細胞與T細胞免疫治療可能進一步加強治療反應。
英文摘要 Abstract

1. Objectives

Immune system plays an important role to eliminate cancer cells. Cancer immunity is a complex mechanism and shows potentials for therapeutic targets. As a traditional model, tumor antigens, captured and processed by dendritic cells, would be presented to effector/memory T cells and cytotoxic T cells, which then recognize and attack tumor cells. Regulatory T cells, however, would repress the other immune cells to prevent excess tissue destruction. Unlike solid tumors, lymphomas are originated from immune system, which might directly influence host immune system and reveal more unpredictable results. Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma and is the most common type of adult lymphoma. Analysis of host immune cells may provide useful information for assessing prognosis or possibly clinical management. In addition, poor immune surveillance is expected to influence on tumor progression. In human beings, brain is an immune-privileged sanctuary, which may contribute to an ineffective host anti-immune response. Therefore, we focused on a specific DLBCL subtype-primary central nervous system (CNS) diffuse large B-cell lymphoma (PCNSL) and compared it to peripheral counterpart.

2. Methods

Peripheral blood samples from 77 DLBCL patients and 30 healthy volunteers were analyzed using flow cytometry immunophenotyping. Complete blood cell counts, T cell subsets, and dendritic cells (DCs) were detected and the results were correlated with clinicopathologic characteristics. In addition, thirty-two biopsy specimens of PCNSL and 30 specimens of low-stage non-CNS DLBCL from immunocompetent patients formed the study group. The density and distribution of immune cells, including dendritic cells (DC-LAMP+ and S100+), effector/memory T-cells (CD45RO+) and cytotoxic T-cells (granzyme B+), and expression of HLA-DR by lymphoma cells were evaluated immunohistochemically.

3. Results

Compared with healthy volunteers, DLBCL patients had significantly higher leukocyte and monocyte counts (P<0.001); higher percentages of neutrophils (P<0.001), “natural” regulatory T cells (Tregs, CD3+Foxp3+, P<0.001), and immature DCs (CD83−CD1a+, P=0.005); and lower percentages of lymphocytes (P<0.001) and helper T cells (P=0.038). In univariate analysis, high neutrophil counts (≧6000/μl, P=0.014) and “induced” Tregs (CD4+CD25+, P=0.026) were poor survival factors along with high IPI scores (P<0.001) and other high-risk clinical parameters. In multivariate analysis, high Tregs retained significance. Suppression of lymphocytes correlated with poor clinical factors; higher natural Tregs correlated with a lower CD4+/CD8+ ratio (P=0.035) and more immature DCs (P=0.055). In PCNSL, patients showed poorer overall survival (P=0.032). Comparing the PCNSL and DLBCL biopsy specimens, the PCNSL cells showed less HLA-DR expression (P=0.003) and there were fewer S100+ cells (P<0.01), and effector T cells (P=0.026) infiltrating PCNSL versus DLBCL. For PCNSL patients, fewer cytotoxic T cells in the background were a poor prognostic factor (P=0.004). Intratumoral S100+-cell infiltration was positively correlated with T-cell infiltration, and a T-cell rimming pattern.

4. Conclusions

Changes in blood immune cells occur in DLBCL patients. The results also support a suppressive role of Tregs in adaptive immunity and correlate with poor-risk prognostic factors. In PCNSL, the baseline anti-tumor immune response is inadequate compared with non-CNS DLBCL and this response may play a role in poorer prognosis. Adjuvant dendritic-cell and T-cell immunotherapy may further boost treatment responses in PCNSL patients.
論文目次 CONTENTS

ABSTRACT IN CHINESE 3
ABSTRACT IN ENGLISH 5
ACKNWLEDGMENT 7
MAIN THESIS 11
1. INTRODUCTION 11
1.1 Diffuse large B-cell lymphoma (DLBCL) 11
1.2 Host immune response in DLBCL 12
1.3 T-cell response and Treg in DLBCL 13
1.4 PCNSL 14
1.5 Specific aims and study design 15
2. MATERIALS AND METHODS 16
2.1 Study subjects 16
2.1.1 Patients and healthy control for flow cytometry 16
2.1.2 Tissue samples from PCNSL cases and their comparisons (non-CNS DLBCL) 16
2.2 Flow cytometry 17
2.3 Immunohistochemical methods for PCNSL cases and their comparisons 18
2.4 Measurements of PCNSL cases and their comparisons 19
2.5 Measurement of caspase 3+ tumor cells and CD123+ DCs in PCNSL 19
2.6 Statistical analysis 20
3. RESULTS 21
3.1 PB immune cells differed between DLBCL patients and healthy volunteers 21
3.2 Clinical factors and PB immune cells correlated with patient survival 21
3.3 PB immune cells correlated with clinical factors 21
3.4 Differences between PCNSL and non-CNS DLBCL 22
3.5 Prognostic factors in PCNSL 22
3.6 Correlation of PCNSL immune cell infiltration and tumor characteristics 23
4. DISCUSSION 24
4.1 Differences in PB immune cells between DLBCL patients and healthy people 24
4.2 PB lymphocyte count and clinical factors 24
4.3 PB Treg in DLBCL patients 24
4.4 Controversial role of Treg in DLBCL patients 25
4.5 Differences between PCNSL patients and its peripheral counterpart 26
4.6 Cytotoxic T-cell infiltration in PCNSL 26
4.7 Unfavorable clinical predictors in PCNSL 27
4.8 Tumor immunophenotype in PCNSL 28
4.9 PCNSL escapes from host immune response 28
4.10 Using S100 as an dendritic cell marker in CNS 29
5. CONCLUSION 30
6. FUTURE WORK 31
REFERENCES 32
TABLES 43
Table 1. Summary of clinical features of DLBCL cases 43
Table 2. Differences between cases and healthy control groups 45
Table 3. Unfavorable clinical and immunocellular factors for DLBCL patients 47
Table 4. Absolute number of neutrophils and various lymphocyte subset 49
Table 5. Summary of clinicopathological features between primary central nervous system (CNS) diffuse large B-cell lymphoma (PCNSL) and non-CNS (peripheral) diffuse large B-cell lymphoma (DLBCL) 50
Table 6. Unfavorable clinicopathologic factors of primary central nervous system diffuse large B-cell lymphoma (PCNSL) 51
Table 7. Controversial roles of Treg in DLBCL patients 53
Table 8. Controversial roles of Cytotoxic T-cell in DLBCL patients 54
FIGURES 55
Figure 1. DC-LAMP+ dendritic cells 55
Figure 2. Differences of peripheral blood cells between DLBCL and healthy people 56
Figure 3. Differences in blood immune cells correlate with overall survival in DLBCL patients 57
Figure 4. Comparisons of HLA-DR expression and immune cell infiltration between PCNSL (left column) and peripheral (non-CNS) DLBCL (right column) 58
Figure 5. Overall survival curves 59
Figure 6. Apoptotic cells by Caspase 3 60
Figure 7. CD123+ plasmacytoid dendritic cells 61
Figure 8. S100+ cells in PCNSL 62
APPENDIX 63
PUBLICATION LIST FOR THIS THESIS 63
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