醫(yī)學(xué)免疫學(xué)課件：腫瘤抗原研究進(jìn)展

1、腫瘤抗原研究進(jìn)展腫瘤抗原類型腫瘤相關(guān)抗原腫瘤相關(guān)抗原(tumor-associated antigen, TAA)，是指在腫瘤細(xì)胞或正常細(xì)胞上存在的抗原分子，包括：胚胎性蛋白、糖蛋白抗原、鱗狀細(xì)胞抗原等，常用于臨床腫瘤的診斷。腫瘤相關(guān)抗原并非腫瘤細(xì)胞所特有，正常細(xì)胞可微量合成，而在腫瘤細(xì)胞增殖時高度表達(dá)，因此稱為相關(guān)抗原。腫瘤特異性抗原腫瘤特異性抗原（tumor specific antigen）指僅表達(dá)于某種腫瘤細(xì)胞表面而不存在于正常細(xì)胞上的新抗原，故又稱獨特腫瘤抗原（unique tumor antigen）。腫瘤抗原的主要代表祁 松楠, 錢忠萍. 肺癌血清自身抗體及其應(yīng)用的研究進(jìn)展 J.

2、 國際檢驗醫(yī)學(xué)雜志, 2014, 35（18）:2506-2509.腫瘤抗原的研究進(jìn)展NY-ESO-1背景介紹NY-ESO-1表位研究NY-ESO-1表達(dá)調(diào)控NY-ESO-1抗原呈遞腫瘤抗原疫苗多抗原聯(lián)合檢測NY-ESO-1的發(fā)現(xiàn)http:/pdb/protein/P78358. Accessed on 15 Dec.New York Esophageal Squamous Cell Carcinoma 1180個氨基酸構(gòu)成的腫瘤共享抗原定位在染色體Xq28上NY-ESO-1的在不同組織中的表達(dá)正常組織中：睪丸RT-PCR, 免疫組織化學(xué)法各類腫瘤NY-ESO-1表達(dá)不一蛋白表達(dá)： mRNA：

3、神經(jīng)母細(xì)胞瘤（82%） 前列腺癌、膀胱癌、乳腺癌滑膜肉瘤（80%） 多發(fā)性骨髓瘤、肝癌高表達(dá)黑色素瘤（46%） 腎癌、白血病、直腸癌、白血病 淋巴瘤組織中低表達(dá)個體病情差異大 NY-ESO-1的免疫原性腫瘤患者存在自發(fā)性體液免疫反應(yīng)50%表達(dá)NY-ESO-1抗原的腫瘤患者病情變化導(dǎo)致抗體水平變化腫瘤患者存在自發(fā)性細(xì)胞免疫反應(yīng)抗體陽性患者中90%產(chǎn)生特異性T細(xì)胞強(qiáng)免疫原性與多表位有關(guān)迄今為止表位最多的腫瘤抗原NY-ESO-1表位研究HLAHLA frequencyPeptide sequencePositionLymphocyte stimulation ReferencesDR93LLEFYL

4、AMPFATPM87-100peptideMizote,2010DR84KEFTVSGNILT124-134peptideMizote,2010DR424PFATPMEAELARR95-107peptideMizote,2010DR118PGVLLKEFTVSGNILTIRLTAADHR119-143peptideAyyoub,2010C1212FATPMEAELAR96-106peptideEikawa, 2013B525FATPMEAEL96-104peptideEikawa, 2013B3520MPFATPMEAEL94-104peptideEikawa,2013A2420YLAMPFA

5、TPME91-101peptideEikawa, 2013/peptide/tumor-specific/ Accessed on 14 Dec.NY-ESO-1表位研究NY-ESO-1f（91-110） vaccine病人的HLA型：A*24:02, B*35:01, B*52:01, C*03:03 and C*12:02注射疫苗提純外周血CD8+T細(xì)胞進(jìn)一步刺激激活CD8+T細(xì)胞克隆擴(kuò)增CD8+T細(xì)胞CD8+T細(xì)胞識別反應(yīng)實驗位點 主型 等位基因序號NY-ESO-1表位研究Eikawa S, Kakimi K, Isobe M, etc. Induction of CD8 T-cell

6、responses restricted to multiple HLA class I alleles in a cancer patient by immun ization with a 20-mer NY-ESO-1f(NY-ESO-191-110) peptide. Int. J. Cancer: 132, 345354 (2013).NY-ESO-1表位研究Eikawa S, Kakimi K, Isobe M, etc. Induction of CD8 T-cell responses restricted to multiple HLA class I alleles in

7、a cancer patient by immun ization with a 20-mer NY-ESO-1f(NY-ESO-191-110) peptide. Int. J. Cancer: 132, 345354 (2013).NY-ESO-1表位研究Eikawa S, Kakimi K, Isobe M, etc. Induction of CD8 T-cell responses restricted to multiple HLA class I alleles in a cancer patient by immun ization with a 20-mer NY-ESO-1

8、f(NY-ESO-191-110) peptide. Int. J. Cancer: 132, 345354 (2013).表位確認(rèn)實驗總結(jié)明確細(xì)胞HLA型抗原呈遞細(xì)胞構(gòu)建特異性T細(xì)胞構(gòu)建計算機(jī)設(shè)計可能表位序列T細(xì)胞識別實驗四聚體確認(rèn)實驗NY-ESO-1表達(dá)調(diào)控表觀遺傳學(xué)機(jī)制DNA去甲基化組蛋白乙?；M蛋白甲基化NY-ESO-1表達(dá)調(diào)控DAC157-165*HLA-A2/HLA-A2Klar AS, Gopinadh J, Kleber S, Wadle A,Renner C. Treatment with 5-Aza-2-Deoxycytidine Induces Expression of

9、 NY-ESO-1 andFacilitates Cytotoxic T Lymphocyte-Mediated TumorCell Killing. PLoS ONE 10(10): e0139221.doi:10.1371/journal.pone.0139221NY-ESO-1抗原呈遞MHC-I類分子的抗原呈遞MHC-II類分子的抗原呈遞APC相關(guān)途徑腫瘤細(xì)胞自身表達(dá)MHC-II分子并呈遞抗原蛋白酶體途徑內(nèi)體/溶酶體相關(guān)途徑自噬途徑，蛋白酶體途徑等NY-ESO-1的抗原呈遞NY-ESO-1（157-170）/HLA-DP4Fonteneau JF, Brilot F, Mnz C, Ga

10、nnag M. The Tumor Antigen NY-ESO-1 Mediate Direct Recognition of Melanoma Cells by CD4+ T Cells after Intercellular Antigen transfer. J Immunol published online 25 November 2015NY-ESO-1的抗原呈遞Fonteneau JF, Brilot F, Mnz C, Gannag M. The Tumor Antigen NY-ESO-1 Mediate Direct Recognition of Melanoma Cel

11、ls by CD4+ T Cells after Intercellular Antigen transfer. J Immunol published online 25 November 2015CQ：一種溶酶體抑制劑NY-ESO-1的抗原呈遞Fonteneau JF, Brilot F, Mnz C, Gannag M. The Tumor Antigen NY-ESO-1 Mediate Direct Recognition of Melanoma Cells by CD4+ T Cells after Intercellular Antigen transfer. J Immunol

12、 published online 25 November 2015Macroautophagy排除實驗GFP-LH3質(zhì)粒轉(zhuǎn)染腫瘤細(xì)胞CQ抑制LH3降解，但不抑制自噬泡形成Atg12 SiRNA轉(zhuǎn)染NY-ESO-1的抗原呈遞Fonteneau JF, Brilot F, Mnz C, Gannag M. The Tumor Antigen NY-ESO-1 Mediate Direct Recognition of Melanoma Cells by CD4+ T Cells after Intercellular Antigen transfer. J Immunol published o

13、nline 25 November 2015Macroautophagy排除實驗CD4+T細(xì)胞識別NY-ESO-1的抗原呈遞Fonteneau JF, Brilot F, Mnz C, Gannag M. The Tumor Antigen NY-ESO-1 Mediate Direct Recognition of Melanoma Cells by CD4+ T Cells after Intercellular Antigen transfer. J Immunol published online 25 November 2015Chaperone-mediated autophagy

14、排除實驗SiRNA干擾LAMP2aCD4+T細(xì)胞識別NY-ESO-1的抗原呈遞Fonteneau JF, Brilot F, Mnz C, Gannag M. The Tumor Antigen NY-ESO-1 Mediate Direct Recognition of Melanoma Cells by CD4+ T Cells after Intercellular Antigen transfer. J Immunol published online 25 November 2015細(xì)胞間傳遞途徑證明熒光乳膠珠吞噬實驗M199系腫瘤細(xì)胞：HLA-DP4+,NY-ESO-1-加入外源NY-ESO-1CD4+細(xì)胞識別NY-ESO-1的抗原呈遞Fonteneau JF, Brilot F, Mnz C, Gannag M. The Tumor Antigen NY-ESO-1 Mediate Direct Recognition of Melanoma Cells by CD4+ T Cells after Intercellular Antigen transfer. J Immunol pu