跳到主要內容

臺灣博碩士論文加值系統

(44.200.194.255) 您好!臺灣時間:2024/07/24 05:07
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:李忠良
研究生(外文):LI, CHUNG-LIANG
論文名稱:探討以去醣基化PD-L1表現來預測晚期乳癌病人接受免疫檢查點抑制劑Atezolizumab(Tecentriq)的藥物反應
論文名稱(外文):De-glycosylated PD-L1 As A Prognostic Biomarker For Responsiveness To Atezolizumab (Tecentriq) In Advanced Breast Cancer Patients
指導教授:潘美仁
指導教授(外文):PAN, MEI-REN
口試委員:侯明鋒郭耀隆
口試委員(外文):HOU, MING-FENGKUO, YAO-LUNG
口試日期:2022-07-15
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:醫學研究所碩士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:英文
論文頁數:58
中文關鍵詞:去醣基化
外文關鍵詞:De-glycosylated
相關次數:
  • 被引用被引用:0
  • 點閱點閱:158
  • 評分評分:
  • 下載下載:9
  • 收藏至我的研究室書目清單書目收藏:0
背景:
在所有乳癌亞型中,以三陰性乳癌的預後為最差。因為缺乏ER/PR/HER2表現,三陰性乳癌病人從前大多只能化療,治療選擇非常受限。但科學家發現在三陰性乳癌中,它有很高的T淋巴球浸潤和高度PD-L1的表現。這兩個特色代表免疫治療也許有助於三陰性乳癌的治療。在Impassion 130中,發現PD-L1陽性的病人對於免疫治療反應較佳。然而近期研究顯示,為了運送和穩定功能上,PD-L1蛋白有高度的醣基化。這進而衍生出一個重要議題,醣基化是否會影響臨床組織中PD-L1的偵測。所以本論文想要去證明去醣基化後的PD-L1會不會增加偵測率並且其表現程度高低是否會和治療反應有關係。
方法:
我們選9位三陰性乳癌的病人,這些病人一開始的PD-L1 表現在IC計分系統上是小於1%。其中8位是轉移性乳癌患者並且至少經過第一線的化療,而另外一位是局部晚期的乳癌病人接受前導性化療。我們收集這9位病人檢體,並且把檢體去醣基化後,來分析去醣基化後PD-L1的變化和治療反應。
結果:
經過去醣基化後,分析四種PD-L1計算方式都有顯著的上升,其p值約在0.036~0.004且上升倍率從2.891到99.611。在和治療反應做比較後,發現在去醣基化後的TPS和H-score-M其數值和治療反應呈現正相關性。接著使用ROC 去分析適合的Cut-off值和最大AUC,結果顯示去醣基化後的TPS值在四種計分方式下最能拿來預測治療反應。
結論:
把PD-L1經去醣基化步驟後,確實可以增加PD-L1偵測率,這方法也提供了臨床醫師可以有更好的偵測方式,來選擇合適的病人來使用免疫療法。在本文中更高的PD-L1表現能帶來比較好的治療反應。去醣基化後的TPS看起來是一個合適的治療反應的預測因子。

Background:
Of all subtypes of breast cancer, triple-negative breast cancer (TNBC) has the worst prognosis. Traditionally, treatments have been limited to chemotherapy, due to lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). However, scientists have detected a high level of T-cell infiltration as well as a high level of programmed death ligand 1 (PD-L1) expression in TNBC. As such, TNBC is a potential candidate for immune therapy. In the IMpassion130 study, a randomized, double-blind, placebo-controlled trial of first-line atezolizumab plus nab-paclitaxel (as compared with placebo plus nab-paclitaxel) in patients with locally advanced or metastatic TNBC, the researchers proved that PD-L1 levels were associated with response to immunotherapy. Moreover, PD-L1 has high glycosylation, thereby enabling transport and maintenance functionality. However, it is concerned whether high glycosylation interferes with the detection rate. Herein, we evaluated the relation between the deglycosylation of PD-L1 and its detection rate, as well as the association between the level of deglycosylated PD-L1 and treatment response.
Methods:
More specifically, we enrolled nine TNBC patients in the current study. These patients underwent PD-L1 SP142 antibody staining and showed a tumor-infiltrating immune cell (IC) score of <1%. Eight metastatic TNBC patients received at least first line chemotherapy, whereas the ninth patient was an advanced TNBC patient receiving neoadjuvant chemotherapy (NAC). We performed deglycosylation of patients’ tissue samples and checked their PD-L1 levels in order to compare treatment response outcomes.
Results:
Following deglycosylation, we found increasing PD-L1 expression according to four score systems (IC, tumor proportion score [TPS], and histoscores [H-score-M, H-score-M+C]), with P-values of 0.036–0.004 and fold changes (FC) of 2.891-99.611. We then evaluated treatment response in regard to PD-L1 levels and noted that the TPS and H-score-M systems, after deglycosylation, had more power to predict treatment response. We also used receiving operating characteristic curves to calculate optimal cut-off levels and areas under the curve. The results showed that, following deglycosylation, TPS was the most powerful predictive factor of the four scoring systems.
Conclusions:
Deglycosylation of PD-L1 increases the PD-L1 detection rate. This method will help physicians choose appropriate patients for immunotherapy. Higher PD-L1 expression indicates a better treatment response, and deglycosylation of TPS may be a good predictor of treatment response.

Contents
中文摘要 4
Abstract 6
Graphical Abstract 8
Abbreviations 9
Introduction 11
Aims of the research 16
Materials and Methods 16
Results 22
Discussion 44
Conclusion 54
References 55

1.DeSantis, C.E., et al., Breast cancer statistics, 2019. CA Cancer J Clin, 2019. 69(6): p. 438-451.
2.台灣衛生福利部108年癌症發生資料. 2021.
3.Wolff, A.C., et al., Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol, 2013. 31(31): p. 3997-4013.
4.Morris, G.J., et al., Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer, 2007. 110(4): p. 876-84.
5.Dent, R., et al., Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res, 2007. 13(15 Pt 1): p. 4429-34.
6.Lin, N.U., et al., Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer, 2008. 113(10): p. 2638-45.
7.Wahba, H.A. and H.A. El-Hadaad, Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med, 2015. 12(2): p. 106-16.
8.Burstein, M.D., et al., Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res, 2015. 21(7): p. 1688-98.
9.Lehmann, B.D., et al., Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest, 2011. 121(7): p. 2750-67.
10.Liu, Y.R., et al., Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer. Breast Cancer Res, 2016. 18(1): p. 33.
11.Mittendorf, E.A., et al., PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res, 2014. 2(4): p. 361-70.
12.Salgado, R., et al., The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol, 2015. 26(2): p. 259-71.
13.Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012. 12(4): p. 252-64.
14.Curiel, T.J., et al., Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med, 2003. 9(5): p. 562-7.
15.Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med, 2002. 8(8): p. 793-800.
16.He, X. and C. Xu, Immune checkpoint signaling and cancer immunotherapy. Cell Res, 2020. 30(8): p. 660-669.
17.Ishida, Y., et al., Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J, 1992. 11(11): p. 3887-95.
18.Dong, H., et al., B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med, 1999. 5(12): p. 1365-9.
19.Alsaab, H.O., et al., PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol, 2017. 8: p. 561.
20.Schmid, P., et al., Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2020. 21(1): p. 44-59.
21.Vennapusa, B., et al., Development of a PD-L1 Complementary Diagnostic Immunohistochemistry Assay (SP142) for Atezolizumab. Appl Immunohistochem Mol Morphol, 2019. 27(2): p. 92-100.
22.Cortes, J., et al., Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet, 2020. 396(10265): p. 1817-1828.
23.Kattla, J.J., Comprehensive Biotechnology (Third Edition). 2011.
24.Asano, N., Glycosidase inhibitors: update and perspectives on practical use. Glycobiology, 2003. 13(10): p. 93R-104R.
25.Lee, H.H., et al., Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy. Cancer Cell, 2019. 36(2): p. 168-178 e4.
26.Xu, J., et al., Removal of N-Linked Glycosylation Enhances PD-L1 Detection in Colon Cancer: Validation Research Based on Immunohistochemistry Analysis. Technol Cancer Res Treat, 2021. 20: p. 15330338211019442.
27.Ou-Yang, F., et al., De-glycosylated membrane PD-L1 in tumor tissues as a biomarker for responsiveness to atezolizumab (Tecentriq) in advanced breast cancer patients. Am J Cancer Res, 2022. 12(1): p. 123-137.
28.Schwartz, L.H., et al., RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer, 2016. 62: p. 132-7.
29.Mittendorf, E.A., et al., Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet, 2020. 396(10257): p. 1090-1100.
30.Detre, S., G. Saclani Jotti, and M. Dowsett, A "quickscore" method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J Clin Pathol, 1995. 48(9): p. 876-8.
31.Hendry, S., et al., Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors. Adv Anat Pathol, 2017. 24(6): p. 311-335.
32.Kang, S.P., et al., Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic. Ann Oncol, 2017. 28(6): p. 1388-1398.
33.Nanda, R., et al., Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol, 2016. 34(21): p. 2460-7.
34.An, H.J., J.W. Froehlich, and C.B. Lebrilla, Determination of glycosylation sites and site-specific heterogeneity in glycoproteins. Curr Opin Chem Biol, 2009. 13(4): p. 421-6.
35.Apweiler, R., H. Hermjakob, and N. Sharon, On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta, 1999. 1473(1): p. 4-8.
36.Jayaprakash, N.G. and A. Surolia, Role of glycosylation in nucleating protein folding and stability. Biochem J, 2017. 474(14): p. 2333-2347.
37.Aricescu, A.R. and R.J. Owens, Expression of recombinant glycoproteins in mammalian cells: towards an integrative approach to structural biology. Curr Opin Struct Biol, 2013. 23(3): p. 345-56.
38.Wang, Y.N., et al., The impact of PD-L1 N-linked glycosylation on cancer therapy and clinical diagnosis. J Biomed Sci, 2020. 27(1): p. 77.
39.Mei, J., et al., A comparability study of natural and deglycosylated PD-L1 levels in lung cancer: evidence from immunohistochemical analysis. Mol Cancer, 2021. 20(1): p. 11.
40.Deng, W., et al., Recombinant Listeria promotes tumor rejection by CD8(+) T cell-dependent remodeling of the tumor microenvironment. Proc Natl Acad Sci U S A, 2018. 115(32): p. 8179-8184.
41.Gruosso, T., et al., Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers. J Clin Invest, 2019. 129(4): p. 1785-1800.
42.Marra, A., G. Viale, and G. Curigliano, Recent advances in triple negative breast cancer: the immunotherapy era. BMC Med, 2019. 17(1): p. 90.
43.Lee, N., et al., Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy. Pathology, 2016. 48(2): p. 177-87.
44.Maibach, F., et al., Tumor-Infiltrating Lymphocytes and Their Prognostic Value in Cutaneous Melanoma. Front Immunol, 2020. 11: p. 2105.
45.Loi, S., et al., Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086. Annals of Oncology, 2017. 28.
46.Du, S., et al., Blockade of Tumor-Expressed PD-1 promotes lung cancer growth. Oncoimmunology, 2018. 7(4): p. e1408747.
47.Wang, X., et al., Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy. Proc Natl Acad Sci U S A, 2020. 117(12): p. 6640-6650.
48.Waterhouse, P., et al., Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science, 1995. 270(5238): p. 985-8.
49.Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010. 363(8): p. 711-23.
50.Weber, J.S., et al., Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol, 2015. 16(4): p. 375-84.
51.Motzer, R.J., et al., Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol, 2015. 33(13): p. 1430-7.
52.Gao, X. and D.F. McDermott, Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma. Expert Opin Biol Ther, 2018. 18(9): p. 947-957.
53.Hellmann, M.D., et al., Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell, 2018. 33(5): p. 853-861 e4.
54.Hellmann, M.D., et al., Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med, 2019. 381(21): p. 2020-2031.
55.Boyer, M., et al., Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score >/= 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study. J Clin Oncol, 2021. 39(21): p. 2327-2338.



QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top