肿瘤细胞治疗研究
英文原题：Prevalence, Immune Checkpoint Expression, and Spatial Interplay of Immune Cells Are Linked to Favorable Tumor Phenotype in 4915 Human Carcinomas.
Prevalence, Immune Checkpoint Expression, and Spatial Interplay of Immune Cells Are Linked to Favorable Tumor Phenotype in 4915 Human Carcinomas.
无监督聚类分析揭示了一个由634名来自几乎所有不同肿瘤类型的患者组成的“聚类a”，其上皮内免疫细胞密度异常高，以独特的相互作用谱为特征，并伴有最高的免疫检查点表达。
尽管越来越多的证据表明，与肿瘤细胞直接接触的免疫细胞亚群（上皮内）能够预测免疫检查点治疗的应答及患者预后，但目前仍缺乏对上皮内免疫细胞及其空间相互作用的全面评估。为评估43种癌种中的上皮内白细胞密度、免疫检查点表达及空间相互作用，本研究采用深度学习框架和BLEACH&STAIN多重荧光免疫组化技术，对4915例组织芯片格式的肿瘤样本进行了分析。该方法通过7轮序贯染色和成像，实现了21种生物标志物的单细胞分辨率定量。免疫细胞和肿瘤细胞被分类为54个亚群。CD8+细胞毒性T细胞、CD4+T辅助细胞、FOXP3+调节性T细胞、CD20+B细胞、M1/M2巨噬细胞和CD11c+树突状细胞的上皮内免疫细胞平均密度在不同肿瘤类型及个体肿瘤之间差异显著。例如，在管状乳腺癌中为88(±90)个细胞/mm²，在结直肠癌中为661(±729)个细胞/mm²，而在不同来源的鳞状细胞癌中高达2325(±2131)个细胞/mm²。无监督聚类分析揭示了一个包含634例来自几乎所有不同肿瘤类型患者的“聚类a”，其上皮内免疫细胞密度异常高，以独特的相互作用谱为特征，并伴有最高的免疫检查点表达。在所有分析的肿瘤类型中，上皮内高度炎症的聚类a与低病理肿瘤分期显著相关（P < .001）。本研究的数据全面描述了43种不同人类癌组织中的上皮内免疫细胞特征，并鉴定出一种炎症性泛癌表型，其特征为上皮内CD8+细胞毒性T细胞、CD4+T细胞、树突状细胞和M2巨噬细胞之间的强相互作用，同时伴有最高水平的TIM3、PD-1和CTLA-4表达，这与良好的肿瘤表型相关。
Although there is rising evidence that immune cell subpopulations that are in direct contact with the tumor cells (intraepithelial) can predict response to immune checkpoint therapy and patients' outcome, a comprehensive assessment of intraepithelial immune cells and their spatial interplay is lacking. To assess intraepithelial leukocyte densities, immune checkpoint expression, and spatial interactions in 43 carcinoma entities, 4915 tumor samples in a tissue microarray format were analyzed using a deep learning framework and BLEACH&STAIN multiplex fluorescence immunohistochemistry. This approach enabled single-cell resolution quantification of 21 biomarkers through 7 sequential staining and imaging rounds. Immune and tumor cells were classified into 54 subpopulations. The mean intraepithelial immune cell density of CD8 + cytotoxic T cells, CD4 + T-helper cells, FOXP3 + regulatory T cells, CD20 + B cells, M1/M2 macrophages, and CD11c + dendritic cells varied markedly between tumor entities and individual tumors. For instance, 88(±90) cells/mm 2 were found in tubular breast cancer, 661(±729) cells/mm 2 in colorectal cancer, and up to 2325(±2131) cells/mm 2 in squamous cell cancers from various origins. Unsupervised cluster analysis revealed a "cluster a" of 634 patients from almost all different tumor entities with an exceptionally high density of intraepithelial immune cells that was characterized by a unique interaction profile along with the highest immune checkpoint expression. Across all analyzed tumor entities, the intraepithelial highly inflamed cluster a was significantly linked to low pathologic tumor stage (P < .001). The data from this study provide a comprehensive characterization of intraepithelial immune cells across 43 different human carcinomas and identified an inflamed pan-cancer phenotype characterized by strong interactions of intraepithelial CD8 + cytotoxic T cells, CD4 + T cells, dendritic cells, and M2 macrophages, along with highest levels of TIM3, PD-1, and CTLA-4 expression that is linked to a favorable tumor phenotype.
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