Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer.
Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer.
复制标题
尿路上皮膀胱癌中非T细胞增长的肿瘤微环境的分子驱动因素。
DOI：
10.1158/2326-6066.cir-15-0274
复制
发表时间：
2016-07
影响因子：
10.1
通讯作者：
Gajewski TF
中科院分区：
文献类型：
--
作者：
Sweis RF;Spranger S;Bao R;Paner GP;Stadler WM;Steinberg G;Gajewski TF
肌层浸润性膀胱癌是一种常见的恶性肿瘤，预后不良，免疫检查点阻断目前显示出希望。尽管PD-1/PD-L1靶向治疗在这种疾病中具有临床活性，但大多数患者并没有受益，耐药机制仍然未知。非T细胞发炎的肿瘤微环境与不良预后和对免疫疗法的抗性相关。在这份报告中，我们确定了与T细胞排斥相关的肿瘤致癌途径。我们首先建立了T细胞炎性膀胱肿瘤可以通过与CD 8 + T细胞浸润一致的免疫基因表达谱来识别。编码免疫检查点蛋白PD-L1、IDO、FOXP 3、TIM 3和LAG 3的基因的上调与T细胞炎症性肿瘤相关，表明对检查点阻断的敏感性。β-连环蛋白、PPAR-γ和FGFR 3通路在非T细胞炎性肿瘤中被激活。两组之间的总体体细胞突变密度没有差异。确定的三种途径代表了肿瘤内在免疫疗法抗性的靶向潜在途径。
Muscle-invasive urothelial bladder cancer is a common malignancy with poor outcomes for which immune checkpoint blockade is now showing promise. Despite clinical activity of PD-1/PD-L1-targeted therapy in this disease, most patients do not benefit and resistance mechanisms remain unknown. The non-T cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies. In this report, we determined tumor-oncogenic pathways correlating with T cell exclusion. We first establish that T-cell-inflamed bladder tumors can be identified by immune gene expression profiling with concordance with CD8+ T cell infiltration. Upregulation of genes encoding immune checkpoint proteins PD-L1, IDO, FOXP3, TIM3, and LAG3 was associated with T-cell-inflamed tumors, suggesting potential for sensitivity to checkpoint blockade. β-catenin, PPAR-γ, and FGFR3 pathways were activated in non-T cell-inflamed tumors. No difference was seen in overall somatic mutational density between groups. The three pathways identified represent targetable potential pathways of tumor-intrinsic immunotherapy resistance.