Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
复制标题
高光谱细胞社会学揭示与肺癌复发相关的肿瘤 - 免疫细胞空间相互作用
DOI：
10.1186/s40425-018-0488-6
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发表时间：
2019-01-16
影响因子：
10.9
通讯作者：
Guillaud, Martial
中科院分区：
文献类型：
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作者：
Enfield, Katey S. S.;Martin, Spencer D.;Guillaud, Martial
肿瘤微环境（tumor microenvironment，TME）是由肿瘤上皮细胞、间质细胞和免疫细胞组成的复杂混合物，其中的免疫成分对肿瘤的进展和患者的预后具有高度的预测作用。在肺癌中，抗PD-1治疗通过激活T细胞对肿瘤细胞的细胞毒性显著改善患者存活。CD 8 + T细胞和靶细胞之间的直接接触是CD 8 + T细胞活性所必需的，表明TME内免疫细胞的空间组织反映了抗肿瘤免疫的关键过程。目前的免疫组织化学（IHC）成像技术识别免疫细胞的数量和密度，但缺乏对细胞-细胞空间关系（或细胞社会学）的评估。然而，免疫功能通常取决于细胞与细胞的接触，并且不能通过简单的细胞密度指标（例如，每mm（2）的细胞数）来解决。为了解决这个问题，我们开发了一个高光谱细胞社会学技术平台，用于分析细胞间的相互作用，在多通道IHC染色tissue.MethodsTissue切片的原发性肿瘤肺腺癌患者已知的临床结果进行染色，使用多重免疫组化CD 3，CD 8和CD 79 a，和高光谱图像分析确定的所有细胞的表型。每个细胞的Voronoi图用于近似细胞边界，并且识别和量化所有相邻细胞的细胞类型。Monte Carlo分析被用来评估是否细胞社会学模式可能是由于随机分布的cells.ResultsHigh密度的肿瘤内CD 8 + T细胞显着相关的非肿瘤复发。与单独的CD 8 + T细胞密度相比，CD 8 + T细胞被肿瘤细胞包围的细胞社会学模式与不复发更显著相关。被肿瘤细胞包围的CD 3 + CD 8- T细胞也与非复发相关，但与单独的细胞密度具有相似的意义。细胞社会学指标改善了12例患者的复发分类。蒙特卡洛重新采样分析确定，这些细胞社会学模式是非random.ConclusionHyperspectral细胞社会学扩展了我们的理解肿瘤细胞和免疫浸润之间的复杂的相互作用。这项技术可以改善对免疫治疗反应的预测，并加深对抗肿瘤免疫的理解。
BackgroundThe tumor microenvironment (TME) is a complex mixture of tumor epithelium, stroma and immune cells, and the immune component of the TME is highly prognostic for tumor progression and patient outcome. In lung cancer, anti-PD-1 therapy significantly improves patient survival through activation of T cell cytotoxicity against tumor cells. Direct contact between CD8+ T cells and target cells is necessary for CD8+ T cell activity, indicating that spatial organization of immune cells within the TME reflects a critical process in anti-tumor immunity. Current immunohistochemistry (IHC) imaging techniques identify immune cell numbers and densities, but lack assessment of cell-cell spatial relationships (or cell sociology). Immune functionality, however, is often dictated by cell-to-cell contact and cannot be resolved by simple metrics of cell density (for example, number of cells per mm(2)). To address this issue, we developed a Hyperspectral Cell Sociology technology platform for the analysis of cell-cell interactions in multi-channel IHC-stained tissue.MethodsTissue sections of primary tumors from lung adenocarcinoma patients with known clinical outcome were stained using multiplex IHC for CD3, CD8, and CD79a, and hyperspectral image analysis determined the phenotype of all cells. A Voronoi diagram for each cell was used to approximate cell boundaries, and the cell type of all neighboring cells was identified and quantified. Monte Carlo analysis was used to assess whether cell sociology patterns were likely due to random distributions of the cells.ResultsHigh density of intra-tumoral CD8+ T cells was significantly associated with non-recurrence of tumors. A cell sociology pattern of CD8+ T cells surrounded by tumor cells was more significantly associated with non-recurrence compared to CD8+ T cell density alone. CD3+CD8- T cells surrounded by tumor cells was also associated with non-recurrence, but at a similar significance as cell density alone. Cell sociology metrics improved recurrence classifications of 12 patients. Monte Carlo re-sampling analysis determined that these cell sociology patterns were non-random.ConclusionHyperspectral Cell Sociology expands our understanding of the complex interplay between tumor cells and immune infiltrate. This technology could improve predictions of responses to immunotherapy and lead to a deeper understanding of anti-tumor immunity.