湖北食管癌HLA-DQB1的基因多态性
1 湖北医科大学第二医院消化内科 湖北省武汉市 430071
2同济医科大学免疫学教研室 湖北省武汉市 430022
3 中国科学院水生生物研究所国家重点实验室 430071
林军，男，1964-12-27生，湖北省蕲春人，汉族. 1987年湖北医科大学本科毕业，1993/1999年分别获得医学硕士、博士学位.
副教授，发表论文30篇.
项目负责人 林军，430071，湖北省武汉市，湖北医科大学第二医院消化内科.
1Department of Gastroenterology, The Second Hospital of Hubei Medical University, Wuhan 430071, Hubei Province, China
2Department of Immunology, Tongji Medical University, Wuhan 430022, Hubei Province, China
3Institute of Water Biology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
Correspondence to Jun Lin, Chang Sheng Deng, Department of Gastroenterology, The Second Hospital of Hubei Medical
University, Wuhan 430071, Hubei Province, China
Tel. 0086-27-87335914 Email.tcrlstwy@public.wh.hb.cn
收稿日期 2000-04-24 接收日期 2000-05-18
Study on the genetic susceptibility of HLA-DQB1 alleles in esophageal cancer of Hubei Chinese Hans
Jun Lin1, Chang-Sheng Deng1, Jie Sun1, Yan Zhou1, Ping Xiong2 and Ya-Ping Wang3
Abstract
AIM To probe into the genetic susceptibility of HLA-DQB1 alleles to esophageal cancer in Hubei Chinese Hans.
METHODS HLA-DQB1 gene polymorphisms were typed by sequence specific primer based polymerase chain reaction, in 42 patients with esophageal neoplasm and 136 normal control subjects. SAS softword (6.12 for window) was used in satistics.
RESULTS Gene frequency (GF) of HLA-DQB1*0301 allele was significantly higher in esophageal neoplasm patients than those in normal controls, 0.2976 vs 0.1875, P=0.046, the odds ratio 1.835, etiologic fraction 0.1354. There was no association between the patients with the controls in the rested HLA-DQB1 alleles, i.e. GF: HLA-DQB1 *0201 (0.0833 vs 0.1016), *0301 (0.2976 vs 0.1875), *0302 (0.0595 vs 0.0859), *0303 (0.2381 vs 0.1875), *0304 (0.0000 vs 0.0039), *0401 (0.0714 vs 0.0469), *0402 (0.0119 vs 0.0156), *0501 (0.0357 vs 0.0703), *0502 (0.0595 vs 0.0664), *0503 (0.0119 vs 0.0195), *0504 (0.0000 vs 0.0039), *0601 (0.0595 vs 0.0781), *0602 (0.0476 vs 0.0742), *0603 (0.0000 vs 0.0078), *0604 (0.0238 vs 0.0508).
CONCLUSION HLA-DQB1*0301 allele is positively susceptibilitive to the esophageal carcinoma patients of Hubei Han Chinese. Individuals carrying HLA-DQB1*0301 may be susceptible to esophageal carcinoma.
Subject headings esophageal neoplasm; aberrant cell; HLA-DQB1; sequence specific primer based polymerase chain reaction; gene amplification; genetic susceptibility; antigens, neoplasm; cell adhesion molecules
Lin J, Deng CS, Sun J, Zhou Y, Xiong P, Wang YP. Study on the genetic susceptibility of HLA-DQB1 alleles in esophageal cancer of Hubei Chinese Hans. Shijie Huaren Xiaohua Zazhi, 2000;8(9):965-968
摘要
目的 从基因水平探讨湖北地区汉族人食管癌HLA-DQB1等位基因的遗传易感性.
方法 运用序列特异性引物聚合酶链反应技术，检测无亲缘关系湖北汉族健康人136例、食管癌组42例患者的HLA-DQB1等位基因. SAS system统计软件数据处理.
结果 湖北汉族人食管癌患者与正常人比较，HLA-DQB1*0301基因频率显著增高(0.2976 vs 0.1875)，P=0.046，OR=1.835，病因分数=0.1354)；两组间HLA-DQB1其余各等位基因分布频率的比较，HLA-DQB1*0201(0.0833 vs 0.1016),*0301(0.2976 vs 0.1875), *0302(0.0595 vs 0859), *0303 (0.2381 vs 0.1875), *0304 (0.0000 vs 0.0039), *0401 (0.0714 vs 0.0469), *0402 (0.0119 vs 0.0156), *0501 (0.0357 vs 0.0703), *0502 (0.0595 vs 0.0664), *0503 (0.0119 vs 0.0195), *0504 (0.0000 vs 0.0039), *0601 (0.0595 vs 0.0781), *0602 (0.0476 vs 0.0742), *0603 (0.0000 vs 0.0078), *0604 (0.0238 vs 0.0508)，差异均无显著性.
结论 HLA-DQB1*0301等位基因与湖北汉族人食管癌正关联，为其易感基因.
主题词 食管肿瘤；畸变细胞；HLA-DQB1；序列特异性引物聚合酶链反应；基因扩增；遗传易感性；抗原，肿瘤；细胞间粘附分子
林军, 邓长生, 孙洁, 周燕, 熊平, 汪亚平. 湖北食管癌HLA-DQB1的基因多态性. 世界华人消化杂志，2000；8(9)：965-968
0 引言
主要组织相容性复合体(major histocompatibility complex, MHC)即人类白细胞抗原(human leucocyte antigen, HLA)编码基因，系迄今所知最为复杂的人类遗传系统. HLA等位基因产物在不同水平参与和介导机体的免疫识别、免疫应答和调控[1-4]. 畸变细胞(aberrant cell)表面的肿瘤抗原(neoantigen)能被宿主HLA系统识别“自我”、“异己”的T细胞识别，一旦肿瘤细胞HLA抗原(分子)表达缺失，可能导致肿瘤逃避免疫监视(escape immunosurveillance)，这对肿瘤生长和转移具有重要的作用[5-10]. HLA作为人类一种遗传标志，有关HLA编码基因与食管癌遗传易感性迄今尚未见报道. 本课题运用序列特异性引物聚合酶链反应(sequence specific primer based polymerase chain reaction, PCR-SSP)技术，研究HLA-DQB1等位基因与湖北汉族人食管癌遗传关联性.
1 材料和方法
1.1 材料 健康对照组：随机选择无亲缘关系湖北汉族健康人136例，其中男62例，女74例，年龄22岁～48岁，平均36岁±6岁. 食管癌组：42例，均为同地区无血缘关系汉族人，男35例，女7例，年龄41岁～80岁，平均60岁±5岁；均经内镜和(或)手术证实，并经病理确诊为食管鳞状细胞癌(squamous cell carcinoma, SCC).
1.2 方法
1.2.1 PCR-SSP技术的HLA-DQB1多态性分析[11-13] 按改进的盐析法或QIAamp Blood Kit(QIAGEN, Germany)从外周血淋巴细胞提取模板DNA，RNA/DNA定量仪(Pharmacia Biotech)测定DNA含量及浓度. 针对HLA-DQB1第2外显子(exon 2)多态性，设计22对SSP(University Hospital of Essen, Germany). 每一PCR反应管中含待测模板基因组DNA 60ng，Taq DNA聚合酶0.5U，dNTP(dATP,dGTP,dCTP,dTTP)各20μmol，SSP 2pmol. PCR反应条件：预变性94℃ 5min；变性94℃ 30s， 退火65℃ 1min，延伸72℃ 1min，共30个循环. 2%琼脂糖凝胶，15V/cm凝胶电泳20min，紫外透射观察结果由SX-300成象系统(上海四星生物技术公司)存储(图1).
1.2.2 PCR-SSP反应质控 假阴性质控：每一个PCR反应中，都含有一对扩增基因和一个保守基因(人生长激素，human growth hormone gene 429bp)的引物. 后者引物序列[14，15]：5＇-primer, 21mer, 5＇-GCC TTC CCA ACC ATT CCC TTA-3＇，Tm 64℃;3＇-primer, 22mer, 5＇-TCA CGG ATT TCT GTT GTG TTTC-3＇，终浓度0.15μmol/L. 每次扩增后，人生长激素基因作为PCR扩增的阳性内参照，均应有阳性条带产物，若这一保守基因扩增受抑，可能出现假阴性结果；同时还有利于纯合子基因型检测的准确性. 假阳性质控：根据扩增DNA片段碱基数(bp)判断.
图1 HLA-DQB1*0201，0301基因型(Lane: 14,15,16,20)
统计学处理 基因分布频率(gene frequence, GF)、表型频率(phenotype frequence, PF)为频次表计数所得；所有比较数据均经SAS system(6.12 for win)统计软件处理，P<0.05为差异有显著性. GF比较有显著性差异时，若OR>1，则计算病因分数(etiologic fraction, EF)；若OR<1时，计算预防分数(preventive fraction, PF).
2 结果
湖北汉族人食管癌与HLA-DQB1等位基因关联(表1)，食管SSC与HLA-DQB1*0301呈阳性关联，EF为0.1354.
表1 湖北地区汉族人食管鳞癌与正常对照组HLA-DQB1等位基因分布比较
*OR=1.835，EF=0.1354
3 讨论
食管癌有家庭集聚现象，患者家族外周血淋巴细胞染色体畸变率较高，提示高发家庭成员体内可能存在导致癌变的内环境. HLA定位于人类第6号染色体短臂6p23片段上，由紧密连锁的共显性复等位基因组成[16，17]，全长3500kb～4000kb，占人类全部信息的千分之一. Ⅱ类基因长约1000kb，编码α链及β链组成的HLA-Ⅱ类分子，可与携有CD4的T细胞相互作用而执行辅助/诱导免疫功能[18-20]. 多数肿瘤特异性细胞毒T淋巴细胞(cytotoxic T lymphocyte, CTL)反应受HLA-Ⅰ类抗原限制，体内、外实验证实肿瘤细胞Ⅰ类抗原表达低下，可能使其逃避宿主免疫监视、易生长及转移[21-32]. CTL识别自发性肿瘤细胞的肿瘤抗CC可被HLA-Ⅰ类等位基因抑制[21]，此时，HLA-A，B，C抗原表达41%缺失、54%表达减少，仅3%表达增强[22]，其β2M mRNA表达也发生障碍.
本研究结果提示：湖北汉族人食管癌与正常人比较，HLA-DQB1*0301基因分布频率明显增高(GF:0.2976 vs 0.1875)，差别有显著性(P=0.046，OR 1.835，EF 0.1354)；高加索人胃腺癌HLA-DQB1*0301基因频率也显著增加[33]，即跨越人种的不同肿瘤遗传易感性与同一等位基因关联的现象，尤其值得深入探讨，其机制可能为连锁不平衡或抗原特异性识别过程中该等位基因介导的改变.
HLA-Ⅰ类分子和细胞间粘附分子(intercellular adhesion molecule 1, ICAM-1)协同表达时，肿瘤复发危险性降低；不然，食管癌复发危险性增高[34]. 癌基因也能抑制HLA分子表达，以避免CTL细胞攻击，T细胞浸润通常被认为是局部HLA-DR抗原的表达[5,35-37]. 局部肿瘤细胞表面HLA-DR表达的免疫反应，可能防止肿瘤浸润性进展；而DR阴性表达是促进食管SCC浸润性发展的重要因素[5，38-41]. 说明肿瘤细胞HLA-DR分子表达的变化，不是肿瘤形成过程所内在的，而可能只是恶性细胞自身的原因，进一步印证肿瘤发生学的分子生物学研究的重要性. HLA表达异常与肿瘤相关抗原的异常表达同步，在转录水平受癌基因、多种细胞因子和遗传成分的调节[5].
免疫治疗的前景主要着眼于使肿瘤细胞易于表达，或增强免疫系统有效识别肿瘤细胞的能力，通过DNA介导基因转移产生外源性HLA基因表达，γ-IFN或类似的细胞因子诱导剂(cytokine inducer)增加内源性HLA分子表达、促进自发性肿瘤的淋巴细胞浸润，从而获得肿瘤细胞免疫原性，使机体免疫系统很快清除变异细胞，可能成为未来食管癌潜在的重要治疗措施[42-50].
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Hum Gene Ther, 1996;7:1895-1905, 百拇医药(林 军1 邓长生1 孙 洁1 周 燕1 熊 平2 汪亚平3 )
2同济医科大学免疫学教研室 湖北省武汉市 430022
3 中国科学院水生生物研究所国家重点实验室 430071
林军，男，1964-12-27生，湖北省蕲春人，汉族. 1987年湖北医科大学本科毕业，1993/1999年分别获得医学硕士、博士学位.
副教授，发表论文30篇.
项目负责人 林军，430071，湖北省武汉市，湖北医科大学第二医院消化内科.
1Department of Gastroenterology, The Second Hospital of Hubei Medical University, Wuhan 430071, Hubei Province, China
2Department of Immunology, Tongji Medical University, Wuhan 430022, Hubei Province, China
3Institute of Water Biology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
Correspondence to Jun Lin, Chang Sheng Deng, Department of Gastroenterology, The Second Hospital of Hubei Medical
University, Wuhan 430071, Hubei Province, China
Tel. 0086-27-87335914 Email.tcrlstwy@public.wh.hb.cn
收稿日期 2000-04-24 接收日期 2000-05-18
Study on the genetic susceptibility of HLA-DQB1 alleles in esophageal cancer of Hubei Chinese Hans
Jun Lin1, Chang-Sheng Deng1, Jie Sun1, Yan Zhou1, Ping Xiong2 and Ya-Ping Wang3
Abstract
AIM To probe into the genetic susceptibility of HLA-DQB1 alleles to esophageal cancer in Hubei Chinese Hans.
METHODS HLA-DQB1 gene polymorphisms were typed by sequence specific primer based polymerase chain reaction, in 42 patients with esophageal neoplasm and 136 normal control subjects. SAS softword (6.12 for window) was used in satistics.
RESULTS Gene frequency (GF) of HLA-DQB1*0301 allele was significantly higher in esophageal neoplasm patients than those in normal controls, 0.2976 vs 0.1875, P=0.046, the odds ratio 1.835, etiologic fraction 0.1354. There was no association between the patients with the controls in the rested HLA-DQB1 alleles, i.e. GF: HLA-DQB1 *0201 (0.0833 vs 0.1016), *0301 (0.2976 vs 0.1875), *0302 (0.0595 vs 0.0859), *0303 (0.2381 vs 0.1875), *0304 (0.0000 vs 0.0039), *0401 (0.0714 vs 0.0469), *0402 (0.0119 vs 0.0156), *0501 (0.0357 vs 0.0703), *0502 (0.0595 vs 0.0664), *0503 (0.0119 vs 0.0195), *0504 (0.0000 vs 0.0039), *0601 (0.0595 vs 0.0781), *0602 (0.0476 vs 0.0742), *0603 (0.0000 vs 0.0078), *0604 (0.0238 vs 0.0508).
CONCLUSION HLA-DQB1*0301 allele is positively susceptibilitive to the esophageal carcinoma patients of Hubei Han Chinese. Individuals carrying HLA-DQB1*0301 may be susceptible to esophageal carcinoma.
Subject headings esophageal neoplasm; aberrant cell; HLA-DQB1; sequence specific primer based polymerase chain reaction; gene amplification; genetic susceptibility; antigens, neoplasm; cell adhesion molecules
Lin J, Deng CS, Sun J, Zhou Y, Xiong P, Wang YP. Study on the genetic susceptibility of HLA-DQB1 alleles in esophageal cancer of Hubei Chinese Hans. Shijie Huaren Xiaohua Zazhi, 2000;8(9):965-968
摘要
目的 从基因水平探讨湖北地区汉族人食管癌HLA-DQB1等位基因的遗传易感性.
方法 运用序列特异性引物聚合酶链反应技术，检测无亲缘关系湖北汉族健康人136例、食管癌组42例患者的HLA-DQB1等位基因. SAS system统计软件数据处理.
结果 湖北汉族人食管癌患者与正常人比较，HLA-DQB1*0301基因频率显著增高(0.2976 vs 0.1875)，P=0.046，OR=1.835，病因分数=0.1354)；两组间HLA-DQB1其余各等位基因分布频率的比较，HLA-DQB1*0201(0.0833 vs 0.1016),*0301(0.2976 vs 0.1875), *0302(0.0595 vs 0859), *0303 (0.2381 vs 0.1875), *0304 (0.0000 vs 0.0039), *0401 (0.0714 vs 0.0469), *0402 (0.0119 vs 0.0156), *0501 (0.0357 vs 0.0703), *0502 (0.0595 vs 0.0664), *0503 (0.0119 vs 0.0195), *0504 (0.0000 vs 0.0039), *0601 (0.0595 vs 0.0781), *0602 (0.0476 vs 0.0742), *0603 (0.0000 vs 0.0078), *0604 (0.0238 vs 0.0508)，差异均无显著性.
结论 HLA-DQB1*0301等位基因与湖北汉族人食管癌正关联，为其易感基因.
主题词 食管肿瘤；畸变细胞；HLA-DQB1；序列特异性引物聚合酶链反应；基因扩增；遗传易感性；抗原，肿瘤；细胞间粘附分子
林军, 邓长生, 孙洁, 周燕, 熊平, 汪亚平. 湖北食管癌HLA-DQB1的基因多态性. 世界华人消化杂志，2000；8(9)：965-968
0 引言
主要组织相容性复合体(major histocompatibility complex, MHC)即人类白细胞抗原(human leucocyte antigen, HLA)编码基因，系迄今所知最为复杂的人类遗传系统. HLA等位基因产物在不同水平参与和介导机体的免疫识别、免疫应答和调控[1-4]. 畸变细胞(aberrant cell)表面的肿瘤抗原(neoantigen)能被宿主HLA系统识别“自我”、“异己”的T细胞识别，一旦肿瘤细胞HLA抗原(分子)表达缺失，可能导致肿瘤逃避免疫监视(escape immunosurveillance)，这对肿瘤生长和转移具有重要的作用[5-10]. HLA作为人类一种遗传标志，有关HLA编码基因与食管癌遗传易感性迄今尚未见报道. 本课题运用序列特异性引物聚合酶链反应(sequence specific primer based polymerase chain reaction, PCR-SSP)技术，研究HLA-DQB1等位基因与湖北汉族人食管癌遗传关联性.
1 材料和方法
1.1 材料 健康对照组：随机选择无亲缘关系湖北汉族健康人136例，其中男62例，女74例，年龄22岁～48岁，平均36岁±6岁. 食管癌组：42例，均为同地区无血缘关系汉族人，男35例，女7例，年龄41岁～80岁，平均60岁±5岁；均经内镜和(或)手术证实，并经病理确诊为食管鳞状细胞癌(squamous cell carcinoma, SCC).
1.2 方法
1.2.1 PCR-SSP技术的HLA-DQB1多态性分析[11-13] 按改进的盐析法或QIAamp Blood Kit(QIAGEN, Germany)从外周血淋巴细胞提取模板DNA，RNA/DNA定量仪(Pharmacia Biotech)测定DNA含量及浓度. 针对HLA-DQB1第2外显子(exon 2)多态性，设计22对SSP(University Hospital of Essen, Germany). 每一PCR反应管中含待测模板基因组DNA 60ng，Taq DNA聚合酶0.5U，dNTP(dATP,dGTP,dCTP,dTTP)各20μmol，SSP 2pmol. PCR反应条件：预变性94℃ 5min；变性94℃ 30s， 退火65℃ 1min，延伸72℃ 1min，共30个循环. 2%琼脂糖凝胶，15V/cm凝胶电泳20min，紫外透射观察结果由SX-300成象系统(上海四星生物技术公司)存储(图1).
1.2.2 PCR-SSP反应质控 假阴性质控：每一个PCR反应中，都含有一对扩增基因和一个保守基因(人生长激素，human growth hormone gene 429bp)的引物. 后者引物序列[14，15]：5＇-primer, 21mer, 5＇-GCC TTC CCA ACC ATT CCC TTA-3＇，Tm 64℃;3＇-primer, 22mer, 5＇-TCA CGG ATT TCT GTT GTG TTTC-3＇，终浓度0.15μmol/L. 每次扩增后，人生长激素基因作为PCR扩增的阳性内参照，均应有阳性条带产物，若这一保守基因扩增受抑，可能出现假阴性结果；同时还有利于纯合子基因型检测的准确性. 假阳性质控：根据扩增DNA片段碱基数(bp)判断.
图1 HLA-DQB1*0201，0301基因型(Lane: 14,15,16,20)
统计学处理 基因分布频率(gene frequence, GF)、表型频率(phenotype frequence, PF)为频次表计数所得；所有比较数据均经SAS system(6.12 for win)统计软件处理，P<0.05为差异有显著性. GF比较有显著性差异时，若OR>1，则计算病因分数(etiologic fraction, EF)；若OR<1时，计算预防分数(preventive fraction, PF).
2 结果
湖北汉族人食管癌与HLA-DQB1等位基因关联(表1)，食管SSC与HLA-DQB1*0301呈阳性关联，EF为0.1354.
表1 湖北地区汉族人食管鳞癌与正常对照组HLA-DQB1等位基因分布比较
| HLA-DQB1 等位基因 | 正常对照组 | 食管鳞癌组 | P | ||||
| N1 | GF(n=256) | PF(n=128)% | N2 | GF(n=84) | PF(n=42)% | ||
| 0201 | 26 | 0.1016 | 19.5312 | 7 | 0.0833 | 16.6667 | >0.05 |
| 0301 | 48 | 0.1875 | 34.3750 | 25 | 0.2976 | 45.2381 | 0.046* |
| 0302 | 22 | 0.0859 | 17.1875 | 5 | 0.0595 | 11.9048 | >0.05 |
| 0303 | 48 | 0.1875 | 36.7188 | 20 | 0.2381 | 42.8571 | >0.05 |
| 0304 | 1 | 0.0039 | 0.7812 | 0 | 0.0000 | 0.0000 | >0.05 |
| 0401 | 12 | 0.0469 | 9.3750 | 6 | 0.0714 | 14.2857 | >0.05 |
| 0402 | 4 | 0.0156 | 3.1250 | 1 | 0.0119 | 2.3810 | >0.05 |
| 0501 | 18 | 0.0703 | 13.2813 | 3 | 0.0357 | 7.1429 | >0.05 |
| 0502 | 17 | 0.0664 | 13.2813 | 5 | 0.0595 | 11.9028 | >0.05 |
| 0503 | 5 | 0.0195 | 3.9062 | 1 | 0.0119 | 2.3810 | >0.05 |
| 0504 | 1 | 0.0039 | 0.7812 | 0 | 0.0000 | 0.0000 | >0.05 |
| 0601 | 20 | 0.0781 | 15.6250 | 5 | 0.0595 | 11.9048 | >0.05 |
| 0602 | 19 | 0.0742 | 14.8438 | 4 | 0.0476 | 9.5238 | >0.05 |
| 0603 | 2 | 0.0078 | 1.5625 | 0 | 0.0000 | 0.0000 | >0.05 |
| 0604 | 13 | 0.0508 | 10.1562 | 2 | 0.0238 | 4.7619 | >0.05 |
*OR=1.835，EF=0.1354
3 讨论
食管癌有家庭集聚现象，患者家族外周血淋巴细胞染色体畸变率较高，提示高发家庭成员体内可能存在导致癌变的内环境. HLA定位于人类第6号染色体短臂6p23片段上，由紧密连锁的共显性复等位基因组成[16，17]，全长3500kb～4000kb，占人类全部信息的千分之一. Ⅱ类基因长约1000kb，编码α链及β链组成的HLA-Ⅱ类分子，可与携有CD4的T细胞相互作用而执行辅助/诱导免疫功能[18-20]. 多数肿瘤特异性细胞毒T淋巴细胞(cytotoxic T lymphocyte, CTL)反应受HLA-Ⅰ类抗原限制，体内、外实验证实肿瘤细胞Ⅰ类抗原表达低下，可能使其逃避宿主免疫监视、易生长及转移[21-32]. CTL识别自发性肿瘤细胞的肿瘤抗CC可被HLA-Ⅰ类等位基因抑制[21]，此时，HLA-A，B，C抗原表达41%缺失、54%表达减少，仅3%表达增强[22]，其β2M mRNA表达也发生障碍.
本研究结果提示：湖北汉族人食管癌与正常人比较，HLA-DQB1*0301基因分布频率明显增高(GF:0.2976 vs 0.1875)，差别有显著性(P=0.046，OR 1.835，EF 0.1354)；高加索人胃腺癌HLA-DQB1*0301基因频率也显著增加[33]，即跨越人种的不同肿瘤遗传易感性与同一等位基因关联的现象，尤其值得深入探讨，其机制可能为连锁不平衡或抗原特异性识别过程中该等位基因介导的改变.
HLA-Ⅰ类分子和细胞间粘附分子(intercellular adhesion molecule 1, ICAM-1)协同表达时，肿瘤复发危险性降低；不然，食管癌复发危险性增高[34]. 癌基因也能抑制HLA分子表达，以避免CTL细胞攻击，T细胞浸润通常被认为是局部HLA-DR抗原的表达[5,35-37]. 局部肿瘤细胞表面HLA-DR表达的免疫反应，可能防止肿瘤浸润性进展；而DR阴性表达是促进食管SCC浸润性发展的重要因素[5，38-41]. 说明肿瘤细胞HLA-DR分子表达的变化，不是肿瘤形成过程所内在的，而可能只是恶性细胞自身的原因，进一步印证肿瘤发生学的分子生物学研究的重要性. HLA表达异常与肿瘤相关抗原的异常表达同步，在转录水平受癌基因、多种细胞因子和遗传成分的调节[5].
免疫治疗的前景主要着眼于使肿瘤细胞易于表达，或增强免疫系统有效识别肿瘤细胞的能力，通过DNA介导基因转移产生外源性HLA基因表达，γ-IFN或类似的细胞因子诱导剂(cytokine inducer)增加内源性HLA分子表达、促进自发性肿瘤的淋巴细胞浸润，从而获得肿瘤细胞免疫原性，使机体免疫系统很快清除变异细胞，可能成为未来食管癌潜在的重要治疗措施[42-50].
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