Immune Cytolytic Activity Stratifies Molecular Subsets of Human Pancreatic Cancer
Immune Cytolytic Activity Stratifies Molecular Subsets of Human Pancreatic Cancer
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DOI：
10.1158/1078-0432.ccr-16-2128
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发表时间：
2017-06-15
影响因子：
11.5
通讯作者：
Vonderheide, Robert H.
中科院分区：
文献类型：
--
作者：
Balli, David;Rech, Andrew J.;Vonderheide, Robert H.
目的：免疫疗法有可能改善胰腺导管腺癌（PDA）的不良预后，但临床试验，包括单药PD-1或PD-L1抑制剂，一直令人失望。我们的目的是研究PDA的免疫景观，因为它涉及到肿瘤生物学的各个方面，包括neoepitope burn.Experimental设计：我们使用公开的表达数据，从134原发切除PDA样本从癌症基因组图谱分层患者根据溶细胞T细胞活性表达指数。我们相关的细胞溶解性免疫活性与突变，结构和新表位的tumor.Results特征：人PDA显示一系列的肿瘤内细胞溶解性T细胞活性。具有低细胞溶解活性的PDA肿瘤表现出显著增加的拷贝数改变，包括MYC和NOTCH 2的复发性扩增以及CDKN 2A/B的复发性缺失和突变。与其他肿瘤类型形成鲜明对比的是，PDA中的高细胞溶解活性与突变负荷或新表位负荷（MHC I类和II类）增加无关。细胞溶解性高的肿瘤表现出增加的多个免疫检查点基因的表达相比，细胞溶解性低的肿瘤，除了PD-L1的表达，这是uniformlylow.Conclusions：这些数据确定了一个子集的人PDA具有高细胞溶解性T细胞活性。PDA中的免疫激活指数与基因组改变呈负相关，而不是与突变负荷或新表位负荷相关，这表明内在致癌过程驱动人PDA中的免疫失活。此外，这些数据强调了PD-L1/PD-1以外的免疫检查点作为这种致命疾病的治疗靶点的潜在重要性。(C)2016年AACR。
Purpose: Immunotherapy has the potential to improve the dismal prognosis in pancreatic ductal adenocarcinoma (PDA), but clinical trials, including those with single-agent PD-1 or PD-L1 inhibition, have been disappointing. Our aim was to examine the immune landscape of PDA as it relates to aspects of tumor biology, including neoepitope burden.Experimental Design: We used publicly available expression data from 134 primary resection PDA samples from The Cancer Genome Atlas to stratify patients according to a cytolytic T-cell activity expression index. We correlated cytolytic immune activity with mutational, structural, and neoepitope features of the tumor.Results: Human PDA displays a range of intratumoral cytolytic T-cell activity. PDA tumors with low cytolytic activity exhibited significantly increased copy number alterations, including recurrent amplifications of MYC and NOTCH2 and recurrent deletions and mutations of CDKN2A/B. In sharp contrast to other tumor types, high cytolytic activity in PDA did not correlate with increased mutational burden or neoepitope load (MHC class I and class II). Cytolytic-high tumors exhibited increased expression of multiple immune checkpoint genes compared to cytolytic-low tumors, except for PD-L1 expression, which was uniformly low.Conclusions: These data identify a subset of human PDA with high cytolytic T-cell activity. Rather than being linked to mutation burden or neoepitope load, immune activation indices in PDA were inversely linked to genomic alterations, suggesting that intrinsic oncogenic processes drive immune inactivity in human PDA. Furthermore, these data highlight the potential importance of immune checkpoints other than PD-L1/PD-1 as therapeutic targets in this lethal disease. (C) 2016 AACR.