Claudin-low bladder tumors are immune infiltrated and actively immune suppressed
Claudin-low bladder tumors are immune infiltrated and actively immune suppressed
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DOI：
10.1172/jci.insight.85902
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发表时间：
2016-03-17
期刊：
影响因子：
8
通讯作者：
Vincent, Benjamin G.
中科院分区：
文献类型：
--
作者：
Kardos, Jordan;Chai, Shengjie;Vincent, Benjamin G.
我们报告发现了一种高级别膀胱癌的claudin-低分子亚型，其与乳腺癌的同型半胱氨酸亚型具有相同的特征。Claudin-低膀胱肿瘤富含多种遗传特征，包括RB 1、EP 300和NCOR 1突变率增加; EGFR扩增频率增加; FGFR 3、ELF 3和KDM 6A突变率降低; PPARG扩增频率降低。虽然低密蛋白肿瘤显示出最高的免疫基因特征表达，但它们也显示出与在主动免疫抑制中观察到的基因表达模式一致的基因表达模式。这似乎不是由于预测的新抗原负荷的差异，而是与细胞因子和趋化因子水平从低PPARG活性的广泛上调相关，从而允许无对抗的NF κ B活性。综上所述，这些结果定义了膀胱癌的分子亚型，其具有不同的分子特征和免疫学特征，理论上，其将引发免疫应答。
We report the discovery of a claudin-low molecular subtype of high-grade bladder cancer that shares characteristics with the homonymous subtype of breast cancer. Claudin-low bladder tumors were enriched for multiple genetic features including increased rates of RB1, EP300, and NCOR1 mutations; increased frequency of EGFR amplification; decreased rates of FGFR3, ELF3, and KDM6A mutations; and decreased frequency of PPARG amplification. While claudin-low tumors showed the highest expression of immune gene signatures, they also demonstrated gene expression patterns consistent with those observed in active immunosuppression. This did not appear to be due to differences in predicted neoantigen burden, but rather was associated with broad upregulation of cytokine and chemokine levels from low PPARG activity, allowing unopposed NFKB activity. Taken together, these results define a molecular subtype of bladder cancer with distinct molecular features and an immunologic profile that would, in theory, be primed for immunotherapeutic response.