Systematic Pan-Cancer Analysis Reveals Immune Cell Interactions in the Tumor Microenvironment.
Systematic Pan-Cancer Analysis Reveals Immune Cell Interactions in the Tumor Microenvironment.
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DOI：
10.1158/0008-5472.can-16-2490
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发表时间：
2017-03-15
期刊：
影响因子：
11.2
通讯作者：
Cheng C
中科院分区：
文献类型：
--
作者：
Varn FS;Wang Y;Mullins DW;Fiering S;Cheng C
随着最近免疫疗法的出现，迫切需要了解泛癌症和组织特异性背景下肿瘤微环境中免疫细胞的相互作用。多维数据集使系统的方法能够在大量患者中剖析这些相互作用，进一步了解患者对实体瘤的免疫反应。使用一种综合方法，我们从癌症基因组图谱中推断出23种肿瘤类型中不同免疫细胞亚群的渗透水平。根据这些数量，我们构建了一个共渗透网络，揭示了肿瘤微环境中细胞溶解细胞和髓系细胞之间的相互作用。通过整合患者突变数据，我们发现，虽然突变负担与不同肿瘤类型之间的免疫渗透差异有关，但其他因素可能解释了起源于相同组织的肿瘤之间的差异。我们通过检查单个免疫细胞亚群的预后价值以及功能不一致的细胞类型的共同渗透如何与患者生存相关来总结这一分析。在多种肿瘤类型中，我们发现CD8+T细胞的保护作用被巨噬细胞和其他类型的髓系细胞共侵袭所严重调制，提示髓系抑制细胞参与了肿瘤的发生发展。我们的发现说明了肿瘤微环境中不同免疫细胞类型之间的复杂相互作用，并表明这些相互作用在患者生存中发挥着重要作用。这些结果表明，在研究肿瘤免疫原性和免疫治疗反应的因素时，个性化免疫反应谱的重要性。
With the recent advent of immunotherapy, there is a critical need to understand immune cell interactions in the tumor microenvironment in both pan-cancer and tissue-specific contexts. Multi-dimensional datasets have enabled systematic approaches to dissect these interactions in large numbers of patients, furthering our understanding of the patient immune response to solid tumors. Using an integrated approach, we inferred the infiltration levels of distinct immune cell subsets in 23 tumor types from The Cancer Genome Atlas. From these quantities, we constructed a co-infiltration network, revealing interactions between cytolytic cells and myeloid cells in the tumor microenvironment. By integrating patient mutation data, we found that while mutation burden was associated with immune infiltration differences between distinct tumor types, additional factors likely explained differences between tumors originating from the same tissue. We concluded this analysis by examining the prognostic value of individual immune cell subsets as well as how co-infiltration of functionally discordant cell types associated with patient survival. In multiple tumor types, we found that the protective effect of CD8+ T cell infiltration was heavily modulated by co-infiltration of macrophages and other myeloid cell types, suggesting the involvement of myeloid-derived suppressor cells in tumor development. Our findings illustrate complex interactions between different immune cell types in the tumor microenvironment and indicate these interactions play meaningful roles in patient survival. These results demonstrate the importance of personalized immune response profiles when studying the factors underlying tumor immunogenicity and immunotherapy response.