Impaired interferon signaling is a common immune defect in human cancer
Impaired interferon signaling is a common immune defect in human cancer
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DOI：
10.1073/pnas.0901329106
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发表时间：
2009-06-02
影响因子：
11.1
通讯作者：
Lee, Peter P.
中科院分区：
文献类型：
--
作者：
Critchley-Thorne, Rebecca J.;Simons, Diana L.;Lee, Peter P.
免疫功能障碍在许多癌症类型的患者中发展，并可能导致肿瘤进展和免疫治疗失败。癌症相关免疫功能障碍的潜在机制尚未完全了解。有效的IFN信号传导对淋巴细胞功能至关重要; IFN信号传导缺陷的动物以更高的速率发展癌症。我们假设IFN信号的改变可能是癌症常见的免疫功能障碍的关键机制。为了解决这个问题，我们评估了3种主要癌症患者外周血淋巴细胞对IFN的功能反应：乳腺癌，黑色素瘤和胃肠道癌。与健康对照组相比，来自所有3个癌症患者组的T细胞和B细胞中I型IFN（IFN-α）诱导的信号传导减少。II型IFN（IFN-γ）诱导的信号传导在来自所有3个癌症患者组的B细胞中减少，但在T细胞或自然杀伤细胞中不减少。受损的IFN信号传导在II、III和IV期乳腺癌患者中同样明显，并且鉴定了T细胞活化的下游功能缺陷。总之，这些发现表明，淋巴细胞IFN信号缺陷出现在乳腺癌，黑色素瘤和胃肠道癌患者，这些缺陷可能代表了一个共同的癌症相关的免疫功能障碍的机制。
Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-alpha)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-gamma)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction.