Novel immune signatures associated with dysplastic naevi and primary cutaneous melanoma in human skin.
Novel immune signatures associated with dysplastic naevi and primary cutaneous melanoma in human skin.
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DOI：
10.1111/exd.13805
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发表时间：
2019-01
影响因子：
3.6
通讯作者：
Krueger JG
中科院分区：
文献类型：
--
作者：
Yan BY;Garcet S;Gulati N;Kiecker F;Fuentes-Duculan J;Gilleaudeau P;Sullivan-Whalen M;Shemer A;Mitsui H;Krueger JG
发育不良痣（DN）是介于普通黑素细胞痣（CMN）和恶性黑色素瘤（MM）之间的具有非典型特征的良性病变。DN是否代表CMN的进行性病变仍有争议。通过基因表达谱和分子基因特征分析，我们的研究揭示了免疫激活和调节的渐进性增加，沿着与黑色素瘤发生有关的途径，从CMN到DN再到MM。使用1.5倍变化和错误发现率≤ 0.05的标准，我们发现了7,186个探针的差异表达从基因组黑色素瘤进展的角度来看，DN和MM之间检测到的差异最大（6，370个独特基因）。尽管T辅助细胞1型（Th 1）诱导基因（IL-12）进行性增加，但RT-PCR表明Th 1或细胞毒性T细胞应答受损一致地，我们的结果表明与调节性T细胞、耗竭的T细胞和致耐受性树突细胞相关的分子标志物进行性增加，包括检测到与MM相关的树突状细胞中细胞因子信号传导抑制因子3（SOCS 3）的表达增加。总而言之，我们的研究结果表明，黑色素瘤免疫抑制微环境的增加可能有助于肿瘤细胞的不受阻碍的增殖。此外，在MM中检测到与致耐受性树突状细胞相关的标记物增加表明，靶向这些抑制性免疫细胞类型可能代表未来免疫治疗的另一种途径。基因表达谱显示，从普通黑素细胞痣到发育不良痣再到黑色素瘤，免疫系统活性逐渐增加，仅在黑色素瘤中出现强烈的负性免疫调节。首次在黑色素瘤树突状细胞中鉴定出细胞因子信号转导抑制因子-3（SOCS 3），为未来的靶向免疫治疗提供了另一种抑制途径。
Dysplastic nevi (DN) are benign lesions with atypical features intermediate between that of common melanocytic nevi (CMN) and malignant melanoma (MM). Debate remains over whether DN represent progressive lesions from CMN. Through gene expression profiling and analysis of molecular gene signatures, our study revealed progressive increases in immune activation and regulation, along with pathways implicated in melanomagenesis, from CMN to DN to MM. Using criteria of 1.5 fold change and false discovery rate ≤ 0.05, we found differential expression of 7,186 probes (6,370 unique genes) with the largest difference detected between DN and MM from the standpoint of genomic melanoma progression. Despite progressive increases in the T-helper type 1 (Th1) inducing gene (IL-12), RT-PCR indicated impaired Th1 or cytotoxic T-cell response (decreased IFN-γ) in MM. Concordantly, our results indicated progressive increases in molecular markers associated with regulatory T-cells, exhausted T-cells, and tolerogenic dendritic cells, including detection of increased expression of suppressor of cytokine signaling 3 (SOCS3) in dendritic cells associated with MM. All together, our findings suggest that the increased immunosuppressive microenvironment of melanoma may contribute to unhampered proliferation of neoplastic cells. In addition, the detection of increased markers associated with tolerogenic dendritic cells in MM suggest that targeting these suppressive immune cell types may represent an alternative avenue for future immunotherapy. Gene expression profiling revealed progressive increases in immune system activity from common melanocytic nevi to dysplastic nevi to melanoma, with negative immunoregulation emerging strongly only in melanoma. The first identification of suppressor of cytokine signaling-3 (SOCS3) in dendritic cells of melanomas represents an alternative suppressor pathway for future targeted immunotherapy.
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