Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer.
Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer.
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DOI：
10.1038/sj.bjc.6600026
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发表时间：
2002-01-07
影响因子：
8.8
通讯作者：
Cannon, M J
中科院分区：
文献类型：
--
作者：
Santin, A D;Bellone, S;Ravaggi, A;Roman, J J;Pecorelli, S;Parham, G P;Cannon, M J
子宫浆液性乳头状癌是子宫内膜癌的一种高度侵袭性变体，在组织学上与高级别卵巢癌相似。然而，与卵巢癌不同的是，它从发病起就是一种对化疗耐药的疾病，对以顺铂为基础的联合化疗的反应率约为20%，预后极差。在这项研究中，我们证明在3例子宫浆液性乳头状癌患者中，肿瘤裂解物脉冲的自体树突状细胞能够引发针对自体肿瘤靶细胞的特异性CD8 + 细胞毒性T淋巴细胞反应。患者1和2的细胞毒性T淋巴细胞（CTL）对自体肿瘤细胞表现出强烈的溶细胞活性，不裂解自体淋巴母细胞或自体EB病毒转化的细胞系，并且对自然杀伤细胞敏感的K - 562细胞系具有不同程度的细胞毒性。患者3的CD8 + T细胞仅在首次致敏时对自体肿瘤细胞表现出适度但可重复的细胞毒性。在主动脉旁淋巴结肿瘤进展后从患者3采集外周血淋巴细胞进行进一步致敏尝试未成功。抗HLA - I类（W6/32）和抗LFA - 1单克隆抗体可显著抑制对自体肿瘤细胞的细胞毒性。患者1和2的高细胞毒性CD8 + T细胞显示出异质性的CD56表达，而患者3的无细胞毒性CD8 + T细胞不表达CD56。通过对单细胞水平的细胞内细胞因子表达进行双色流式细胞术分析，在患者1和2的细胞毒性T淋巴细胞群体中可检测到干扰素 - γ表达细胞占显著优势，而在患者3中始终检测到一个主要表达白细胞介素 - 4和白细胞介素 - 10的CD8 + T细胞群体。综上所述，这些数据表明肿瘤裂解物脉冲的树突状细胞可成为诱导子宫浆液性乳头状癌特异性CD8 + 细胞毒性T淋巴细胞的有效工具，这些细胞毒性T淋巴细胞能够在体外杀伤自体肿瘤细胞。然而，一些患者中高水平的肿瘤特异性耐受可能对治疗性疫苗接种构成重大障碍。这些结果可能对采用主动或过继免疫疗法辅助治疗子宫浆液性乳头状癌患者具有重要意义。
《英国癌症杂志》（2002年）86卷，151 - 157页。DOI: 10.1038/sj/bjc/6600026 www.bjcancer.com
© 2002癌症研究运动
Uterine serous papillary carcinoma is a highly aggressive variant of endometrial cancer histologically similar to high grade ovarian cancer. Unlike ovarian cancer, however, it is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and an extremely poor prognosis. In this study, we demonstrate that tumour lysate-pulsed autologous dendritic cells can elicit a specific CD8+ cytotoxic T lymphocyte response against autologous tumour target cells in three patients with uterine serous papillary cancer. CTL from patients 1 and 2 expressed strong cytolytic activity against autologous tumour cells, did not lyse autologous lymphoblasts or autologous EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Patient 3 CD8+ T cells expressed a modest but reproducible cytotoxicity against autologous tumour cells only at the time of the first priming. Further priming attempts with PBL collected from patient 3 after tumour progression in the lumboaortic lymph nodes were unsuccesful. Cytotoxicity against autologous tumour cells could be significantly inhibited by anti-HLA class I (W6/32) and anti-LFA-1 MAbs. Highly cytotoxic CD8+ T cells from patients 1 and 2 showed a heterogeneous CD56 expression while CD56 was not expressed by non-cytotoxic CD8+ T cells from patient 3. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, a striking dominance of IFN-γ expressors was detectable in CTL populations of patients 1 and 2 while in patient 3 a dominant population of CD8+ T cells expressing IL-4 and IL-10 was consistently detected. Taken together, these data demonstrate that tumour lysate-pulsed DC can be an effective tool in inducing uterine serous papillary cancer-specific CD8+ CTL able to kill autologous tumour cells in vitro. However, high levels of tumour specific tolerance in some patients may impose a significant barrier to therapeutic vaccination. These results may have important implications for the treatment in the adjuvant setting of uterine serous papillary cancer patients with active or adoptive immunotherapy. British Journal of Cancer (2002) 86, 151–157. DOI: 10.1038/sj/bjc/6600026 www.bjcancer.com © 2002 The Cancer Research Campaign