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目的研究热休克凋亡自体食管癌肿瘤细胞抗原负载的树突状细胞(dendritic cell,DC)对激发食管癌患者特异性免疫应答的影响及治疗的临床疗效。方法选择2010年11月至2013年6月就诊的手术治疗后食管鳞癌患者40例,随机分为研究组(28例)与对照组(12例)。对照组行常规放疗,研究组采用放疗联合DC免疫治疗:(1)留取自体食管癌组织,经热休克处理(42℃,3 h)后获得热休克凋亡食管癌抗原;(2)分离、培养外周血单个核细胞,其中贴壁细胞经过重组人粒细胞-单核细胞集落刺激因子(rh GM-CSF)、白细胞介素(IL)-4联合诱导为DC;(3)负载热休克抗原,培养1周后经患者腹股沟皮内注射,1周注射1次,共注射4次。在治疗后1周进行迟发型超敏反应(DTH)检测;在患者治疗前后进行血清中细胞因子和抗原特异性IFN-γ+CD8+T细胞检测,并进行免疫学疗效评价。治疗后跟踪随访2年,对远期疗效进行评价。结果 28例研究组食管癌患者对DC治疗耐受良好,治疗后患者血清中Th1型细胞因子(IL-2、IL-12、INF-γ)水平较治疗前和对照组治疗后均有显著提高(P均<0.01)。治疗后研究组IFN-γ+CD8+T细胞比例较对照组有显著提高(P<0.01),其中10例患者IFN-γ+CD8+T细胞比例升高2倍以上。12例食管癌患者DTH试验呈阳性反应,其中9例IFN-γ+CD8+T细胞比例升高2倍以上。定期随访2年,两组均无脱落病例。研究组1年内死亡5例,存活82.14%;2年内共死亡9例,存活67.86%。对照组1年内死亡6例,存活50.00%;2年内共死亡8例,存活33.33%。研究组随访2年时生存比例大于对照组(P<0.05)。结论负载食管癌肿瘤细胞热休克凋亡抗原的DC能激发患者的特异性免疫应答、诱导Th1型细胞因子的分泌,联合放疗远期疗效良好,是一种安全的治疗方法。
Objective To investigate the effect of dendritic cells (DCs) loaded with heat shock and apoptosis on the specific immune response in patients with esophageal cancer and the clinical therapeutic effect. Methods Forty esophageal squamous cell carcinoma patients who underwent surgical treatment from November 2010 to June 2013 were randomly divided into study group (28 cases) and control group (12 cases). The control group received routine radiotherapy. Radiotherapy combined with DC immunotherapy was used in the study group. (1) The esophageal cancer tissues were obtained from esophageal cancer tissues and heat shock treated with heat shock (42 ℃ for 3 h). (2) , Cultured peripheral blood mononuclear cells, in which adherent cells were induced to DC by recombinant human granulocyte-monocyte colony-stimulating factor (rh GM-CSF) and interleukin (IL) -4; (3) Antigen 1 week after culture in patients with inguinal intradermal injection, 1 week injection, a total of 4 times. Delayed-type hypersensitivity (DTH) was detected at 1 week after treatment. Serum cytokines and antigen-specific IFN-γ + CD8 + T cells were detected before and after treatment, and immunological efficacy was evaluated. After follow-up after treatment for 2 years, the long-term efficacy was evaluated. Results Twenty-eight study groups were well tolerated with DC. The levels of Th1 cytokines (IL-2, IL-12, INF-γ) in patients with esophageal cancer were significantly higher than those before treatment and after treatment (P <0.01). After treatment, the proportion of IFN-γ + CD8 + T cells in the study group was significantly higher than that in the control group (P <0.01). The proportion of IFN-γ + CD8 + T cells in the 10 patients was more than twice as high. DTH test was positive in 12 patients with esophageal cancer, in which the proportion of 9 cases of IFN-γ + CD8 + T cells increased more than 2 times. Regular follow-up of 2 years, no shedding cases in both groups. In the study group, 5 patients died in one year and survived 82.14%. Nine patients died in 2 years and survived 67.86%. In the control group, 6 patients died within 1 year and survived 50.00%. In the 2 years, 8 patients died and 33.33% survived. The survival rate of the study group at 2 years follow-up was greater than that of the control group (P <0.05). Conclusions DCs carrying heat shock apoptotic antigen in esophageal cancer cells can stimulate the specific immune response of patients and induce the secretion of Th1 type cytokines. The long-term combined effect of radiotherapy is a safe treatment.