Critchley-Thorne Rebecca J, Yan Ning, Nacu Serban, Weber Jeffrey, Holmes Susan P, Lee Peter P
Division of Hematology, Department of Medicine, Stanford University, Stanford, California, United States of America.
PLoS Med. 2007 May;4(5):e176. doi: 10.1371/journal.pmed.0040176.
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-alpha was significantly reduced (Delta = 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-alpha that is achievable only in IFN therapy used in melanoma. The lowest responders to IFN-alpha in the Phosflow assay also showed the lowest gene expression in response to IFN-alpha. 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-gamma, and tumor necrosis factor alpha, 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.
免疫系统功能障碍在多种癌症中均有记录。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。
为深入了解癌症中免疫功能障碍的分子机制，将12例黑色素瘤患者的纯分选外周血淋巴细胞的基因表达谱与12例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25个显著改变的基因中，17个是干扰素（IFN）刺激基因。这些微阵列结果通过定量PCR和对IFN的功能反应得到进一步证实。在磷酸化流式细胞分析中，与健康对照（n = 9）相比，黑色素瘤患者（n = 9）中因干扰素-α而磷酸化STAT1的淋巴细胞的中位数百分比显著降低（Δ = 16.8%；95%置信区间，0.98%至33.35%）。磷酸化流式细胞分析结果还确定了黑色素瘤患者的两个亚组：IFN反应型（33%）和低IFN反应型（66%）。黑色素瘤患者组中IFN信号传导的缺陷在IFN刺激基因的表达水平上通过仅在黑色素瘤中使用的IFN治疗中可达到的高浓度IFN-α的延长刺激而部分得到克服。磷酸化流式细胞分析中对IFN-α反应最低的患者在对IFN-α的基因表达方面也最低。最后，与对照相比，低IFN反应患者的T细胞表现出功能异常，包括活化标志物CD69、CD25和CD71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，以及抗CD3/CD28抗体刺激后存活率降低。
干扰素信号传导缺陷代表癌症中免疫功能障碍的新的主要机制。这些发现可用于设计对抗黑色素瘤免疫功能障碍的疗法并改善癌症免疫治疗。
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