Analysis and characterization of antitumor T-cell response after administration of dendritic cells loaded with allogeneic tumor lysate to metastatic melanoma patients
Analysis and characterization of antitumor T-cell response after administration of dendritic cells loaded with allogeneic tumor lysate to metastatic melanoma patients
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DOI：
10.1097/cji.0b013e318159f5ba
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发表时间：
2008-01-01
影响因子：
3.9
通讯作者：
Tartour, Eric
中科院分区：
文献类型：
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作者：
Bercovici, Nadege;Haicheur, Nacilla;Tartour, Eric
癌症疫苗的主要目标是诱导对肿瘤相关抗原 (TAA) 具有特异性的 CDS+ T 细胞，但由于离体检测的灵敏度较低，因此很难对这些细胞进行表征。在这里，我们重点关注黑色素瘤患者在接种含有同种异体肿瘤细胞系裂解物（Lysate-DC）的自体树突状细胞后的 TAA 特异性 CD8（+）T 细胞反应。在接受治疗的 40 名患者中，有 16 名患者对肿瘤细胞裂解物和/或分化特异性 CD8(+) T 细胞和癌睾丸抗原产生了免疫反应。体外致敏后，通过干扰素（IFN）-γ酶联免疫斑点检测TAA特异性CD8（+）T细胞反应，该反应要么在治疗期间短暂，要么延迟，即在所有疫苗接种完成后观察到。我们无法将这些免疫反应与临床数据关联起来，因为根据实体瘤标准中的反应评估标准，没有患者达到总体客观反应。据报道，3 名患者病情稳定，10 名患者表现出抗肿瘤活性的证据。我们发现 4 名患者体内的 TAA 特异性 T 细胞在体外产生穿孔素，但在酶联免疫斑点中不产生 IFN-γ。病毒特异性 T 细胞也观察到 IFN-γ 和穿孔素的差异表达。总而言之，我们的结果表明，Lysatc-DC 疗法引发了肿瘤特异性 CDS+ T 细胞，不限于人类白细胞抗原 A2(+) 患者，声波 T 细胞仅在再刺激后才在体外分泌和 IFN-γ。抗肿瘤和抗病毒CD8+T细胞对穿孔素和IFN-γ的差异表达表明，单独使用IFN-γ的产生来监测T细胞会忽视疫苗引发的功能性T细胞亚群。
The primary goal of cancer vaccines is to induce CDS+ T cells specific for tumor-associated antigens (TAA) but the characterization of these cells has been difficult because of the low sensitivity of ex vivo assays. Here, we focused on TAA-specific CD8(+) T-cell responses in melanoma patients after vaccination with autologous dendritic cells loaded with lysates derived from allogeneic tumor-cell lines (Lysate-DC). Out of 40 patients treated, 16 patients developed immune response to tumor-cell lysate and/or CD8(+) T cells specific for differentiation and cancer-testis antigens. TAA-specific CD8(+) T-cell responses were detected by interferon (IFN)-gamma enzyme-linked immunospot after in vitro sensitization and were, either transient during the treatment period or delayed, that is, observed after completion of all vaccinations. We Could not correlate these immune responses to clinical data as none of the patients achieved an overall objective response according to Response Evaluation Criteria in Solid Tumors criteria. Three patients were reported as stable disease and 10 patients presented evidence of antitumor activity. We found that TAA-specific T cells characterized in 4 patients produced perforin ex vivo, but no IFN-gamma in enzyme-linked immunospot. Differential expression of IFN-gamma and perforin was also observed for viral-specific T cells. Altogether, our results show that Lysatc-DC therapy elicited tumor-specific CDS+ T cells nonlimited to human leukocyte antigen-A2(+) patients, with sonic T cells secreting perform ex vivo and IFN-gamma only after restimulation. The differential expression of perforin and IFN-gamma by antitumor and antiviral CD8(+) T cells supports that the sole use of IFN-gamma production to monitor T cells overlooks functional T-cell subpopulations triggered by vaccines.