Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma.
Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma.
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DOI：
10.1371/journal.pmed.0040176
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发表时间：
2007-05
期刊：
影响因子：
15.8
通讯作者：
Lee PP
中科院分区：
文献类型：
--
作者：
Critchley-Thorne RJ;Yan N;Nacu S;Weber J;Holmes SP;Lee PP
免疫系统的功能障碍在许多类型的癌症中都有记载。癌症状态下免疫功能障碍的确切性质和分子基础尚不清楚。为了深入了解癌症中免疫功能障碍的分子机制，我们将12名黑色素瘤患者的纯分类外周血淋巴细胞的基因表达谱与12名健康对照进行了比较。在黑色素瘤患者的T细胞和B细胞中有25个显著改变的基因，其中17个是干扰素（IFN）刺激的基因。这些微阵列的发现被定量PCR和对ifn的功能反应进一步证实。在Phosflow分析中，黑色素瘤患者（n = 9）与健康对照组（n = 9）相比，对干扰素-α产生磷酸化STAT1反应的淋巴细胞的中位数百分比显著降低（Δ = 16.8%； 95%可信区间，0.98%至33.35%）。Phosflow结果还确定了黑色素瘤患者的两个亚组：ifn反应（33%）和低ifn反应（66%）。通过高浓度IFN-α的长时间刺激，在IFN刺激基因的表达水平上部分克服了整个黑色素瘤患者组中IFN信号传导的缺陷，这只有在用于黑色素瘤的IFN治疗中才能实现。Phosflow实验中对IFN-α反应最低的基因表达量也最低。最后，来自低ifn应答患者的T细胞表现出功能异常，包括活化标志物CD69、CD25和CD71的表达降低；TH1细胞因子，白细胞介素-2，IFN-γ和肿瘤坏死因子α，与对照组相比，抗cd3 /CD28抗体刺激后生存率降低。干扰素信号的缺陷代表了癌症中免疫功能障碍的新的、主要的机制。这些发现可能用于设计治疗方法，以抵消黑色素瘤的免疫功能障碍，并改善癌症免疫治疗。由于T细胞和B细胞中干扰素反应基因表达模式的改变，Peter Lee及其同事发现黑色素瘤患者的淋巴细胞在干扰素信号传导方面存在缺陷。免疫系统除了对抗感染外，还是人体抵御癌症的主要屏障之一。在癌症发展过程中，正常细胞获得基因变化，使它们能够不受控制地生长并在体内移动。其中一些变化改变了它们表面表达的抗原（免疫系统识别的蛋白质）。结果，免疫系统识别并消除新形成的癌细胞。当这种免疫监视失败时，肿瘤——大量癌细胞——就会出现。例如，一些肿瘤通过改变它们表达的抗原来躲避免疫系统。其他的释放因子关闭免疫反应。然而，对于许多肿瘤类型，尚不清楚为什么免疫监视在其发展过程中失败，或者为什么在大多数晚期疾病患者中出现整体免疫抑制。科学家们想要了解癌症患者免疫功能障碍的分子基础，因为如果他们知道免疫系统出了什么问题，他们可能就能修复它。此外，对癌症的免疫疗法也有相当大的兴趣，例如，用干扰素（由某些免疫系统细胞产生的蛋白质，可以激活其他免疫细胞，也可以杀死肿瘤细胞）治疗和开发疫苗来刺激抗肿瘤免疫反应。到目前为止，免疫疗法还不是很成功，可能是因为癌症患者的免疫系统存在潜在的功能障碍。了解这种功能障碍可能会导致免疫治疗的改进，因此在这项研究中，研究人员调查了转移性黑色素瘤（一种致命的皮肤癌）患者免疫功能障碍的分子机制。研究人员从转移性黑色素瘤患者和健康人的血液中纯化淋巴细胞（参与抗肿瘤反应的免疫细胞），并使用一种称为微阵列表达谱的技术检查他们的基因表达模式。黑色素瘤患者体内的CD8 T细胞（杀死表达外来或改变抗原的细胞）、CD4 T细胞（帮助其他T淋巴细胞和B淋巴细胞完成自己的工作）和B细胞（制造抗体和蛋白质，识别抗原并标记癌细胞，以便免疫系统消灭它们）的24种基因表达水平均低于健康个体，而其中一种基因表达水平高于健康个体。这些基因中有17个是干扰素刺激基因，它们编码负责干扰素作用的蛋白质。因此，研究人员检查了患者和控制淋巴细胞对干扰素的功能反应。当干扰素与淋巴细胞结合时，它会触发在STAT1蛋白上添加一个磷酸基团，然后诱导基因表达的变化。在对干扰素-α（有时用于治疗黑色素瘤）的反应中，患者淋巴细胞中STAT1磷酸化的比例低于对照淋巴细胞。三分之一患者的淋巴细胞对干扰素-α反应良好，而其他患者的淋巴细胞反应甚微。此外，长期高浓度的干扰素-α治疗部分克服了患者淋巴细胞中干扰素信号传导的缺陷。最后，患者的T细胞在暴露于激活刺激后不能产生正常的免疫细胞激活标记或细胞因子（介导肿瘤细胞杀伤的蛋白质），与对照淋巴细胞相比，生存率降低。这些结果表明，对于转移性黑色素瘤患者，干扰素信号缺陷是免疫功能障碍的重要因素。他们还表明，来自黑色素瘤患者（特别是那些对干扰素-α反应较差的患者）的T细胞具有功能异常，使它们不太可能识别和处理黑色素瘤细胞。这些结果需要在更多的患者中得到证实，但它们仍然代表了理解与晚期黑色素瘤和其他肿瘤相关的免疫功能障碍的重要一步。此外，干扰素应答者和干扰素不良应答者这两组患者的鉴定可能解释了为什么只有一些黑色素瘤患者从干扰素-α治疗中获益。因此，有可能通过检查患者淋巴细胞的干扰素反应性来预先选择那些将从这种治疗（有一些严重的副作用）中受益的患者。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0040176访问这些网站。美国国家癌症研究所信息（英语和西班牙语），为患者提供免疫系统及其参与癌症的信息，为患者和黑色素瘤专业人士提供美国癌症协会信息，为患者提供免疫治疗癌症研究所（纽约）基于网络的关于癌症和免疫系统的书MedlinePlus百科全书页面关于黑色素瘤（英语和西班牙语）英国癌症研究所患者信息关于黑色素瘤，包括免疫治疗的信息
Dysfunction of the immune system has been documented in many types of cancers. The precise nature and molecular basis of immune dysfunction in the cancer state are not well defined. To gain insights into the molecular mechanisms of immune dysfunction in cancer, gene expression profiles of pure sorted peripheral blood lymphocytes from 12 patients with melanoma were compared to 12 healthy controls. Of 25 significantly altered genes in T cells and B cells from melanoma patients, 17 are interferon (IFN)-stimulated genes. These microarray findings were further confirmed by quantitative PCR and functional responses to IFNs. The median percentage of lymphocytes that phosphorylate STAT1 in response to interferon-α was significantly reduced (Δ = 16.8%; 95% confidence interval, 0.98% to 33.35%) in melanoma patients (n = 9) compared to healthy controls (n = 9) in Phosflow analysis. The Phosflow results also identified two subgroups of patients with melanoma: IFN-responsive (33%) and low-IFN-response (66%). The defect in IFN signaling in the melanoma patient group as a whole was partially overcome at the level of expression of IFN-stimulated genes by prolonged stimulation with the high concentration of IFN-α that is achievable only in IFN therapy used in melanoma. The lowest responders to IFN-α in the Phosflow assay also showed the lowest gene expression in response to IFN-α. Finally, T cells from low-IFN-response patients exhibited functional abnormalities, including decreased expression of activation markers CD69, CD25, and CD71; TH1 cytokines interleukin-2, IFN-γ, and tumor necrosis factor α, and reduced survival following stimulation with anti-CD3/CD28 antibodies compared to controls. Defects in interferon signaling represent novel, dominant mechanisms of immune dysfunction in cancer. These findings may be used to design therapies to counteract immune dysfunction in melanoma and to improve cancer immunotherapy. Prompted by altered expression patterns of interferon-responsive genes in T and B cells, Peter Lee and colleagues find that lymphocytes from melanoma patients have defects in interferon signaling. The immune system, in addition to fighting infections, provides one of the body's main defenses against cancer. During cancer development, normal cells acquire genetic changes that allow them to grow uncontrollably and to move around the body. Some of these changes alter the antigens (proteins recognized by the immune system) expressed on their surface. As a result, the immune system recognizes and eliminates the newly formed cancer cells. Tumors—large masses of cancer cells—occur when this immune surveillance fails. Some tumors, for example, hide from the immune system by altering the antigens they express. Others release factors that shut off the immune response. However, for many tumor types, it is not clear why immune surveillance fails during their development or why global immune suppression develops in most patients with advanced disease. Scientists want to understand the molecular basis of immune dysfunction in patients with cancer because if they knew what had gone wrong with the immune system, they might be able to repair it. Also, there is considerable interest in immunotherapy for cancer—for example, treatment with interferons (proteins made by certain immune system cells that activate other immune cells and also kill tumor cells) and the development of vaccines to stimulate antitumor immune responses. So far, immunotherapy has not been very successful, probably because of the underlying dysfunction of the immune system in patients with cancer. Understanding this dysfunction might lead to improvements in immunotherapy, so in this study the researchers have investigated the molecular mechanism responsible for immune dysfunction in patients with metastatic melanoma, a deadly form of skin cancer. The researchers purified lymphocytes (immune cells that are involved in antitumor responses) from the blood of patients with metastatic melanoma and healthy people and examined their patterns of gene expression using a technique called microarray expression profiling. CD8 T cells (which kill cells expressing foreign or altered antigens), CD4 T cells (which help other T and B lymphocytes do their jobs), and B cells (which make antibodies, proteins that recognize antigens and label cancer cells for destruction by the immune system) from patients with melanoma all expressed lower levels of 24 genes, and higher levels of one gene, than those from healthy individuals. 17 of these genes were interferon-stimulated genes, which encode proteins responsible for the effects of interferons. Therefore, the researchers checked the functional responses of patient and control lymphocytes to interferon. When interferon binds to lymphocytes, it triggers the addition of a phosphate group to the protein STAT1, which then induces changes in gene expression. STAT1 phosphorylation occurred in a lower percentage of patient lymphocytes than control lymphocytes in response to interferon-α (which is sometimes used to treat melanoma). The lymphocytes from one-third of the patients responded well to interferon-α, but those from the other patients showed little response. Furthermore, prolonged treatment with high concentrations of interferon-α partly overcame the defect in interferon signaling in patient lymphocytes. Finally, T cells from the patients failed to make the normal markers of immune cell activation or cytokines (proteins that mediate the killing of tumor cells) after exposure to activating stimuli and had reduced survival compared to control lymphocytes. These results indicate that for patients with metastatic melanoma defects in interferon signaling are an important contributor to immune dysfunction. They also show that T cells from patients with melanoma (particularly those who respond poorly to interferon-α) have functional abnormalities that make them less likely to recognize and deal with melanoma cells. These results need confirming in many more patients, but they nevertheless represent an important step toward understanding the immune dysfunction associated with advanced melanoma and possibly other tumors. In addition, the identification of two subgroups of patients—interferon responders and poor interferon responders—may explain why only some patients with melanoma benefit from treatment with interferon-α. It might, therefore, be possible to pre-select those who would benefit from this treatment (which has some serious side effects) by examining patient lymphocytes for interferon responsiveness. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040176. US National Cancer Institute information (in English and Spanish) for patients on the immune system and its involvement in cancer, and for patients and professionals on melanoma American Cancer Society information for patients on immunotherapy Cancer Research Institute (New York) web-based book on cancer and the immune system MedlinePlus encyclopedia pages on melanoma (in English and Spanish) Cancer Research UK patient information on melanoma, including information on immunotherapy
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DOI：
10.1084/jem.188.12.2357
发表时间：
1998-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hung K;Hayashi R;Lafond-Walker A;Lowenstein C;Pardoll D;Levitsky H
通讯作者：
Levitsky H
影响因子：
20.3
作者：
Cassatella, MA;Gasperini, S;Yoshimura, A
通讯作者：
Yoshimura, A
影响因子：
158.5
作者：
Gogas, H;Ioannovich, J;Kirkwood, JM
通讯作者：
Kirkwood, JM
影响因子：
2.1
作者：
Kendziorski, CM;Zhang, Y;Attie, AD
通讯作者：
Attie, AD
影响因子：
56.9
作者：
Hahne, M;Rimoldi, D;Tschopp, J
通讯作者：
Tschopp, J