Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade
Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade
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DOI：
10.1101/056101
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发表时间：
2016-05
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影响因子：
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通讯作者：
P. Charoentong;F. Finotello;Mihaela Angelova;Clemens Mayer;M. Efremova;D. Rieder;H. Hackl;Z. Trajanoski
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文献类型：
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作者：
P. Charoentong;F. Finotello;Mihaela Angelova;Clemens Mayer;M. Efremova;D. Rieder;H. Hackl;Z. Trajanoski
癌症基因组图谱揭示了常见人类癌症的基因组图谱。与此同时，使用检查点阻滞剂的免疫疗法正在改变晚期癌症的治疗方式。由于只有一小部分患者对检查点阻滞剂有反应，识别预测标志物和耐药机制是一个紧张的研究课题。为了便于了解肿瘤与免疫细胞的相互作用，我们对20例实体癌的瘤内免疫环境和肿瘤抗原进行了表征，并创建了肿瘤免疫图谱(http://tcia.at).免疫浸润物的细胞特征揭示了癌症胚系抗原在自发免疫中的作用，并表明肿瘤基因决定免疫表型和肿瘤逃逸机制。利用机器学习，我们确定了肿瘤免疫原性的决定因素，并开发了一种称为免疫表观评分的量化评分方案。在两个独立的验证队列中，免疫表型评分是抗CTLA-4和抗PD-1抗体应答的更好的预测因子。我们的发现和开发的资源可能有助于为癌症免疫治疗提供信息，并促进精确免疫肿瘤学的发展。
The Cancer Genome Atlas revealed the genomic landscapes of common human cancers. In parallel, immunotherapy with checkpoint blockers is transforming the treatment of advanced cancers. As only a minority of the patients is responsive to checkpoint blockers, the identification of predictive markers and the mechanisms of resistance is a subject of intense research. To facilitate understanding of the tumor-immune cell interactions, we characterized the intratumoral immune landscapes and the cancer antigenomes from 20 solid cancers, and created The Cancer Immunome Atlas (http://tcia.at). Cellular characterization of the immune infiltrates revealed a role of cancer-germline antigens in spontaneous immunity and showed that tumor genotypes determine immunophenotypes and tumor escape mechanisms. Using machine learning we identified determinants of tumor immunogenicity and developed a scoring scheme for the quantification termed immunophenoscore. The immunophenoscore was superior predictor of response to anti-CTLA-4 and anti-PD-1 antibodies in two independent validation cohorts. Our findings and the developed resource may help informing cancer immunotherapy and facilitate the development of precision immune-oncology.