An immunogenomic stratification of colorectal cancer: Implications for development of targeted immunotherapy.
An immunogenomic stratification of colorectal cancer: Implications for development of targeted immunotherapy.
复制标题
结直肠癌的免疫基因组分层：对靶向免疫疗法发展的影响。
DOI：
10.4161/2162402x.2014.976052
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发表时间：
2015-03
期刊：
影响因子：
7.2
通讯作者：
Middleton GW
中科院分区：
文献类型：
--
作者：
Lal N;Beggs AD;Willcox BE;Middleton GW
尽管肿瘤浸润性淋巴细胞(TIL)密度对结直肠癌(CRC)有预后和预测作用，但肿瘤遗传学对结直肠癌免疫生物学的影响尚不清楚。识别影响肿瘤免疫表型的遗传因素对于提高分层免疫治疗方法的有效性至关重要。我们对癌症基因组图谱(TCGA)中的CRC数据进行了生物信息学分析，包括二维分层聚类，以定义免疫签名，我们使用该签名来表征关键患者群体的免疫反应。一种名为协调免疫反应簇(CIRC)的免疫特征由28个基因组成，在患者群体中进行协调调节。根据聚集性表达划分出四个患者组。微卫星不稳定(MSI-H)和POL突变患者的A组表现出高CIRC表达，包括几个抑制分子的存在：CTLA4、PDL1、PDL2、LAG3和TIM3。相反，在CIRC表达较低的患者组中，RAS突变丰富。这项工作将大肠肿瘤发生的遗传学和免疫生物学联系起来，并对分层免疫治疗方法的发展产生了影响。微卫星不稳定性和POL突变与高突变负荷和高免疫渗透有关，但所观察到的抑制途径的协调表达表明，联合检查点阻断治疗可能需要提高疗效。相反，RAS突变的肿瘤预示着相对较差的免疫渗透和低抑制分子的表达。在这种情况下，检查点封锁可能不那么有效，这突显了这一患者群体对新策略的要求。
Although tumor infiltrating lymphocyte (TIL) density is prognostic and predictive in colorectal cancer (CRC), the impact of tumor genetics upon colorectal immunobiology is unclear. Identification of genetic factors that influence the tumor immunophenotype is essential to improve the effectiveness of stratified immunotherapy approaches. We carried out a bioinformatics analysis of CRC data in The Cancer Genome Atlas (TCGA) involving two-dimensional hierarchical clustering to define an immune signature that we used to characterize the immune response across key patient groups. An immune signature termed The Co-ordinate Immune Response Cluster (CIRC) comprising 28 genes was coordinately regulated across the patient population. Four patient groups were delineated on the basis of cluster expression. Group A, which was heavily enriched for patients with microsatellite instability (MSI-H) and POL mutations, exhibited high CIRC expression, including the presence of several inhibitory molecules: CTLA4, PDL1, PDL2, LAG3, and TIM3. In contrast, RAS mutation was enriched in patient groups with lower CIRC expression. This work links the genetics and immunobiology of colorectal tumorigenesis, with implications for the development of stratified immunotherapeutic approaches. Microsatellite instability and POL mutations are linked with high mutational burden and high immune infiltration, but the coordinate expression of inhibitory pathways observed suggests combination checkpoint blockade therapy may be required to improve efficacy. In contrast, RAS mutant tumors predict for a relatively poor immune infiltration and low inhibitory molecule expression. In this setting, checkpoint blockade may be less efficacious, highlighting a requirement for novel strategies in this patient group.