The microenvironment of human neuroblastoma supports the activation of tumor-associated T lymphocytes.
The microenvironment of human neuroblastoma supports the activation of tumor-associated T lymphocytes.
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DOI：
10.4161/onci.23618
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发表时间：
2013-03-01
期刊：
影响因子：
7.2
通讯作者：
Levitskaya J
中科院分区：
文献类型：
--
作者：
Carlson LM;De Geer A;Sveinbjørnsson B;Orrego A;Martinsson T;Kogner P;Levitskaya J
淋巴细胞的肿瘤浸润与神经母细胞瘤 (NB) 儿童临床结果的改善有关，但从未证明 T 细胞激活发生在 NB 微环境中。在这里，我们表明，从代表 NB 所有遗传亚群的病变中获得的肿瘤相关淋巴细胞 (TAL) 和在肿瘤切除当天分析的自体外周血淋巴细胞 (PBL) 在组成、表型和功能特征方面存在差异。 NB 微环境似乎促进 CD3+CD8+ T 细胞的积累，并含有较大比例的表达白细胞介素 2 受体 α 链 (CD25) 并表现出效应记忆 (CCR7−CD45RA−) 表型的 T 细胞。因此，在短期培养中用自体肿瘤细胞刺激PBL会增加效应记忆T细胞的比例，上调CD25，刺激TH1细胞因子干扰素γ和肿瘤坏死因子α的表达，并减少转化生长因子β的表达。原发性肿瘤中 TAL 的免疫组织化学染色揭示了原位增殖以及 T 细胞受体在与恶性细胞接触部位聚集的特征模式，表明 NB 环境与免疫系统的激活相容。我们的结果与 CD8+ T 细胞在 NB 微环境中被特异性激活的假设相一致，这似乎允许效应记忆反应。
Tumor infiltration by lymphocytes has been linked to improved clinical outcome in children with neuroblastoma (NB) but T-cell activation has never been demonstrated to occur within the NB microenvironment. Here we show that tumor-associated lymphocytes (TALs) obtained from lesions representing all genetic subsets of NB and autologous peripheral blood lymphocytes (PBLs) analyzed on the day of tumor excision differed in composition, phenotype and functional characteristics. The NB microenvironment appeared to promote the accumulation of CD3+CD8+ T cells and contained a larger proportion of T cells expressing the interleukin-2 receptor α chain (CD25) and manifesting an effector memory (CCR7−CD45RA−) phenotype. Accordingly, the stimulation of PBLs with autologous tumor cells in short-term cultures increased the proportion of effector memory T cells, upregulated CD25, stimulated the expression of the TH1 cytokines interferon γ and tumor necrosis factor α, and reduced the expression of transforming growth factor β. In situ proliferation as well as a characteristic pattern of T-cell receptor aggregation at the contact sites with malignant cells was revealed by the immunohistochemical staining of TALs in primary tumors, indicating that the NB milieu is compatible with the activation of the immune system. Our results are compatible with the hypothesis that CD8+ T cells are specifically activated within the NB microenvironment, which appears to be permissive for effector memory responses.