Intratumoral Cytokines and Tumor Cell Biology Determine Spontaneous Breast Cancer-Specific Immune Responses and Their Correlation to Prognosis
Intratumoral Cytokines and Tumor Cell Biology Determine Spontaneous Breast Cancer-Specific Immune Responses and Their Correlation to Prognosis
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DOI：
10.1158/0008-5472.can-09-1627
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发表时间：
2009-11-01
期刊：
影响因子：
11.2
通讯作者：
Beckhove, Philipp
中科院分区：
文献类型：
--
作者：
Domschke, Christoph;Schuetz, Florian;Beckhove, Philipp
已经描述了癌症患者中的自发免疫应答。然而，它们的临床相关性和产生条件仍不清楚。我们描述了决定原发性乳腺癌患者免疫反应的条件。我们在207名未经治疗的患者和12个Her-2/neu特异性CD 8 T细胞系中使用四聚体分析、体外IFN-γ ELISPOT、细胞毒性测定和ELISA来评估骨髓中的肿瘤特异性T细胞（TC）或血液中的MUC 1特异性抗体。进行多重分析以定量27种肿瘤内细胞因子、趋化因子和生长因子。结果与患者和肿瘤的多个病理和临床参数进行比较。40%的患者表现出肿瘤特异性TC反应。这些与高分化、雌激素受体表达和低增殖活性的肿瘤相关，并且与降低的癌症死亡风险相关。高肿瘤细胞分化与肿瘤内IFN-α浓度升高相关，而与血浆浓度无关，与转化生长因子（TGF）β 1浓度降低相关。在体外引发实验中，这两种细胞因子分别增加或抑制树突状细胞诱导肿瘤反应性TC的能力。在50%的患者中可检测到肿瘤特异性B细胞反应，主要是IgM同种型，并与晚期肿瘤分期、TGF β 1升高、IFN-α降低和TIC反应缺失相关。我们在这里表明，不同类型的免疫应答与不同的细胞因子微环境有关，并与肿瘤病理生物学中的凋亡相关差异相关。这些发现揭示了免疫应答与癌症预后之间的关系。[Cancer Res 2009;69（21）：8420-8]
Spontaneous immune responses in cancer patients have been described. Yet their clinical relevance and the conditions for their generation remain unclear. We characterized conditions that determine immune responses in primary breast cancer patients. We used tetramer analysis, ex vivo IFN-gamma ELISPOT, cytotoxicity assays, and ELISA in 207 untreated patients and 12 Her-2/neu-specific CD8 T-cell lines to evaluate tumor-specific T cells (TC) in the bone marrow or MUC1-specific antibodies in the blood. Multiplex analysis was performed to quantify 27 intratumoral cytokines, chemokines, and growth factors. Results were compared with multiple pathologic and clinical parameters of the patients and tumors. Forty percent of the patients showed tumor-specific TC responses. These correlated with tumors of high differentiation, estrogen receptor expression, and low proliferative activity, and with a reduced cancer mortality risk. High tumor cell differentiation correlated with increased intratumoral, but not plasma, concentrations of IFN-alpha and reduced transforming growth factor (TGF)beta 1. In an in vitro priming experiment these two cytokines increased or inhibited, respectively, the capacity of dendritic cells to induce tumor-reactive TC. Tumor-specific B-cell responses, mainly of IgM isotype, were detectable in 50% of the patients and correlated with advanced tumor stage, increased TGF beta 1, reduced IFN-alpha, and absence of TIC responses. We show here that different types of immune responses are linked to distinct cytokine microenvironments and correlate with prognosis-relevant differences in tumor pathobiology. These findings shed light on the relation between immune response and cancer prognosis. [Cancer Res 2009;69(21):8420-8]