PTEN functions as a melanoma tumor suppressor by promoting host immune response
PTEN functions as a melanoma tumor suppressor by promoting host immune response
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DOI：
10.1038/onc.2013.409
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发表时间：
2014-09-18
期刊：
影响因子：
8
通讯作者：
Wajapeyee, N.
中科院分区：
文献类型：
--
作者：
Dong, Y.;Richards, J-A E.;Wajapeyee, N.
癌细胞获得了几种使其能够存活和进展的特性，包括逃避宿主免疫反应的能力。然而，癌细胞逃避宿主免疫反应的机制在很大程度上仍然不清楚。在此我们研究恶性黑色素瘤细胞中的免疫逃避现象。我们发现肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）是宿主针对黑色素瘤细胞免疫反应的重要调节因子。从机制上讲，PTEN通过阻断磷脂酰肌醇 - 3 - 激酶（PI3K）通路来抑制免疫抑制性细胞因子的表达。在缺乏PTEN的黑色素瘤细胞中，信号转导和转录激活因子3以PI3K依赖的方式激活免疫抑制性细胞因子的转录。此外，来自PTEN缺陷的、源自患者的短期黑色素瘤培养物以及已建立的黑色素瘤细胞系的条件培养基抑制了人单核细胞衍生的树突状细胞中白细胞介素 - 12（IL - 12）的产生。通过恢复PTEN或使用针对免疫抑制性细胞因子的中和抗体可挽救对IL - 12产生的抑制。此外，我们报道PTEN作为一种促进宿主针对癌细胞免疫反应的替代机制，可抑制程序性细胞死亡1配体的表达，程序性细胞死亡1配体是一种已知的宿主免疫反应抑制因子。最后，为了确定我们研究结果的临床意义，我们分析了有或没有强烈宿主反应的恶性黑色素瘤患者样本。这些分析证实，与有强烈宿主反应的样本相比，PTEN缺失与更高比例的无强烈宿主反应的恶性黑色素瘤样本相关。总之，这些结果表明PTEN作为黑色素瘤肿瘤抑制因子，部分是通过调节宿主针对黑色素瘤细胞的免疫反应来发挥作用的，并强调了在招募黑色素瘤患者进行免疫治疗之前评估PTEN状态的重要性。
Cancer cells acquire several traits that allow for their survival and progression, including the ability to evade the host immune response. However, the mechanisms by which cancer cells evade host immune responses remain largely elusive. Here we study the phenomena of immune evasion in malignant melanoma cells. We find that the tumor suppressor phosphatase and tensin homolog (PTEN) is an important regulator of the host immune response against melanoma cells. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, conditioned media from PTEN-deficient, patient-derived short-term melanoma cultures and established melanoma cell lines blocked the production of the interleukin-12 (IL-12) in human monocyte-derived dendritic cells. Inhibition of IL-12 production was rescued by restoring PTEN or using neutralizing antibodies against the immunosuppressive cytokines. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response. Finally, to establish the clinical significance of our results, we analyzed malignant melanoma patient samples with or without brisk host responses. These analyses confirmed that PTEN loss is associated with a higher percentage of malignant melanoma samples with non-brisk host responses compared with samples with brisk host responses. Collectively, these results establish that PTEN functions as a melanoma tumor suppressor in part by regulating the host immune response against melanoma cells and highlight the importance of assessing PTEN status before recruiting melanoma patients for immunotherapies.