Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers.
Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers.
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DOI：
10.1158/1078-0432.ccr-17-0162
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发表时间：
2017-08-01
期刊：
影响因子：
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通讯作者：
Witkiewicz AK
中科院分区：
文献类型：
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作者：
Knudsen ES;Vail P;Balaji U;Ngo H;Botros IW;Makarov V;Riaz N;Balachandran V;Leach S;Thompson DM;Chan TA;Witkiewicz AK
胰腺导管腺癌(PDAC)与支持免疫系统逃避和疾病进展的免疫抑制环境有关。在这里，我们询问了PDAC的遗传、间质和免疫学特征，以描述对预后的影响和更有效地应用免疫治疗的方法。109例PDAC病例被标记为总体生存，作为初步发现的队列。基因表达分析定义了在癌症基因组图谱数据集中确认的PDAC的免疫学亚型。通过组织学分析和免疫组织化学染色评价PDAC的间质和代谢特点。淋巴细胞计数，CD8、FOXP3、CD68、CD163、PDL1、CTLA4染色为免疫浸润性改变。通过对整个外显子组测序数据的分析确定新抗原。采用随机森林聚类法确定多标记亚型，单变量和多变量分析询问预后意义。PDAC患者表现出不同的间质表型，这些表型与预后、糖酵解和低氧生物标志物以及免疫浸润物的组成有关。免疫渗入在不同的PDAC病例中是不同的，M2巨噬细胞和选定的免疫检查点调节因子的丰富与生存特定相关。结合新抗原负荷、免疫学和间质特征的综合分析确定了可能与免疫治疗方法敏感性有关的PDAC新亚型。此外，新抗原水平低且淋巴细胞浸润量最少的亚型与总存活率的提高有关。PDAC的突变负荷与不同的免疫抑制机制有关，这些机制受肿瘤间质环境的影响。所确定的亚型对免疫疗法在PDAC治疗中的应用具有重要意义。
Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunological features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy. A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunological subtypes of PDAC that were confirmed in the Cancer Genome Atlas data set. Stromal and metabolic characteristics of PDAC cases were evaluated by histological analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neo-antigens were determined by analysis of whole exome sequencing data. Random-forest clustering was employed to define multi-marker subtypes, with univariate and multivariate analyses interrogating prognostic significance. PDAC cases exhibited distinct stromal phenotypes that were associated with prognosis, glycolytic and hypoxic biomarkers and immune infiltrate composition. Immune infiltrate was diverse among PDAC cases and enrichment for M2 macrophages and select immune checkpoints regulators were specifically associated with survival. Composite analysis with neo-antigen burden, immunological, and stromal features defined novel subtypes of PDAC that could have bearing on sensitivity to immunological therapy approaches. Additionally, a subtype with low levels of neo-antigens and minimal lymphocyte infiltrate was associated with improved overall survival. The mutational burden of PDAC is associated with distinct immunosuppressive mechanisms that are conditioned by the tumor stromal environment. The defined subtypes have significance for utilizing immunotherapy in the treatment of PDAC.