Evolution of Metastases in Space and Time under Immune Selection
Evolution of Metastases in Space and Time under Immune Selection
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DOI：
10.1016/j.cell.2018.09.018
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发表时间：
2018-10-18
期刊：
影响因子：
64.5
通讯作者：
Galon, Jerome
中科院分区：
文献类型：
--
作者：
Angelova, Mihaela;Mlecnik, Bernhard;Galon, Jerome
我们在一个结直肠癌的纵向数据集中研究了免疫微环境如何塑造不同转移器官中的肿瘤演化。通过多重分析，我们表明转移进展过程中的克隆演化模式取决于转移部位的免疫环境。在免疫评分高以及Ki67（+）肿瘤细胞和CD3（+）细胞空间邻近的部位观察到了新抗原耗竭的遗传学证据。经过免疫编辑的肿瘤克隆被清除且未复发，而进展中的克隆具有免疫特权，尽管存在肿瘤浸润淋巴细胞。对具有免疫特权的转移灶的特征描述揭示了肿瘤内在和外在的逃逸机制。最低的复发风险与高免疫评分、免疫编辑的发生以及低肿瘤负荷相关。我们提出了一个转移进展的平行选择模型，其中分支演化可追溯到免疫逃逸克隆。这些发现可以为理解癌症扩散以及免疫疗法的开发提供信息。
We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67(+) tumor cells and CD3(+) cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.