Molecular Analysis of Tumor-Promoting CD8+ T Cells in Two-Stage Cutaneous Chemical Carcinogenesis
Molecular Analysis of Tumor-Promoting CD8+ T Cells in Two-Stage Cutaneous Chemical Carcinogenesis
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DOI：
10.1038/jid.2009.362
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发表时间：
2010-06-01
影响因子：
6.5
通讯作者：
Girardi, Michael
中科院分区：
文献类型：
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作者：
Kwong, Bernice Y.;Roberts, Scott J.;Girardi, Michael
T-pro 是肿瘤浸润性 TCR αβ(+)CD8(+) 细胞，其细胞毒性潜力降低，可促进实验性两阶段化学皮肤癌发生。为了了解其作用机制，本研究使用全基因组表达分析将 T-pro 与来自多组荷瘤小鼠的全身性 CD8(+) T 细胞进行比较。 T-pro 显示出明显的 T 辅助细胞 17 样特征（高视黄酸相关孤儿受体 (ROR)gamma t、IL-17A、IL-17F；低 T-bet 和脱中胚层蛋白）、调节潜力（高 FoxP3、IL-10、Tim-3）和编码上皮生长因子的转录物（双调蛋白、Gro-1、Gro-2）。三色流式细胞术随后证实肿瘤浸润淋巴细胞（TIL）中存在 TCR β（+）CD8（+）IL-17（+）T 细胞。此外，对乳头状瘤与癌的独立 TIL 分离物进行的时间过程分析揭示了“T-pro 表型”与恶性进展的明显关联。T-pro 的这种分子特征为阐明炎症对皮肤癌发生的作用奠定了基础，并可能为癌症免疫治疗提供有用的生物标志物，其中广泛提倡使用肿瘤特异性 CD8(+) 溶细胞 T 细胞可能会适应细胞对 T-pro 的潜在腐败。该数据也可能与银屑病密切相关，其中表皮可能被产生 CD8(+) IL-17 的 T 细胞浸润。
T-pro are tumor-infiltrating TCR alpha beta(+)CD8(+) cells of reduced cytotoxic potential that promote experimental two-stage chemical cutaneous carcinogenesis. Toward understanding their mechanism of action, this study uses whole-genome expression analysis to compare T-pro with systemic CD8(+) T cells from multiple groups of tumor-bearing mice. T-pro show an overt T helper 17-like profile (high retinoic acid-related orphan receptor-(ROR)gamma t, IL-17A, IL-17F; low T-bet and eomesodermin), regulatory potential (high FoxP3, IL-10, Tim-3), and transcripts encoding epithelial growth factors (amphiregulin, Gro-1, Gro-2). Tricolor flow cytometry subsequently confirmed the presence of TCR beta(+) CD8(+) IL-17(+) T cells among tumor-infiltrating lymphocytes (TILs). Moreover, a time-course analysis of independent TIL isolates from papillomas versus carcinomas exposed a clear association of the "T-pro phenotype'' with malignant progression. This molecular characterization of T-pro builds a foundation for elucidating the contributions of inflammation to cutaneous carcinogenesis, and may provide useful biomarkers for cancer immunotherapy in which the widely advocated use of tumor-specific CD8(+) cytolytic T cells should perhaps accommodate the cells' potential corruption toward the T-pro phenotype. The data are also likely germane to psoriasis, in which the epidermis may be infiltrated by CD8(+) IL-17-producing T cells.