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摘要:
数字病理凭借其便捷的存储、管理、浏览、传输等特点，为远程病理会诊及联合会诊带来了新契机。然而，显微镜的视场有限，在保证分辨率的前提下，无法兼顾全景成像。全景数字病理的提出弥补了这一缺陷，其在保证分辨率的同时可兼顾全景成像。但单张切片仅能实现单靶点检测，而疾病诊断需同时观测多个靶点的表达情况。近年来，多靶点全景数字病理技术发展迅速，因其在药物研发、临床科研以及基础科研等领域有巨大的应用潜力而广受关注。该系统凭借视场大、颜色多、通量高的特点，可在短时间内原位检测整张组织切片上的多种生物标记物的表达情况，借以识别组织上每个细胞表型、丰度、状态及其相互关系。本文首先梳理了数字病理、全景数字病理以及多靶点全景数字病理的发展过程，并简要介绍发展过程中技术的更新迭代，以及发展多靶点全景数字病理的重要性。然后，分别从生物样本准备、多色光学成像以及图像处理3个部分重点介绍多靶点全景数字病理。接下来，阐述了多靶点全景数字病理在肿瘤微环境与肿瘤分子分型等生物医学领域的应用情况。最后，对多靶点全景数字病理的技术优势、目前面临的挑战及其未来的发展趋势进行了总结。
Abstract:Digital pathology has brought new opportunities for remote pathological consultation and joint consultation owing to its convenient storage, management, browsing and transmission. However, because of the limited field of view of a microscope, panoramic imaging cannot be achieved while ensuring a high resolution. The proposal of panoramic digital pathology makes up for this defect and achieves panoramic imaging while ensuring high resolution. However, a single slice can only detect a single target, and disease diagnosis needs to observe the expression of multi-target at the same time. In recent years, multi-target panoramic digital pathology technology has developed rapidly. It has attracted much attention because of its great application potential in drug research and development, clinical research and basic research. Owing to its large field of view, wide range of colors and high flux, the system can detect the expression of various biomarkers on a whole tissue section in situ in a short time to identify the phenotype, abundance, state, and relationship of each cell. Firstly, this paper reviews the development process of digital pathology, panoramic digital pathology and multi-target panoramic digital pathology, as well as the update and iteration of technology in the development process, and illustrates the importance of developing multi-target panoramic digital pathology. Then, the multi-target panoramic digital pathology is described in detail from three perspectives: biological sample preparation, multi-color imaging system and image processing. Next, the applications of multi-target panoramic digital pathology in biomedical fields, such as tumor microenvironments and tumor molecular typing are described. Finally, the advantages, challenges and future development of multi-target panoramic digital pathology are summarized.
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图 2 基于TSA的多重荧光免疫组化流程
Figure 2. Multiplex fluorescent immunohistochemistry based on TSA
表 1 靶点选择原则
Table 1. Target selection principles
疾病 靶点 功能 表达部位 非小细
胞癌[22]CK 一种细胞角蛋白，是上皮来源的肿瘤标志物[23] 主要在上皮细胞中表达的中间丝蛋白[23] CD68 巨噬细胞标记物[24] 存在于骨髓和神经的吞噬细胞[25] Siglec-15 作为免疫调节靶点在肿瘤微环境能
抑制抗原特异性T细胞反应[22]骨髓细胞，人类癌细胞和肿瘤浸润性骨髓细胞[22] 肝癌
组织[26]PD-L1 对抗PD-1/PD-L1治疗反应的预测性生物标志物[27] 骨髓、淋巴、正常上皮细胞和癌症中
组成型表达或诱导的共抑制受体[27]CD68 同上 同上 CD33 髓系细胞分化抗原[28] 主要分布在髓系血细胞[28] CD57 人类自然杀伤细胞标记物[29] 人类自然杀伤细胞和T淋巴细胞[29] CD11b 粘附分子和介导多种配体识别的膜受体[30] 在吞噬细胞、B细胞和T细胞的次要亚群以及自然杀伤细胞上表达[30] CD20 B细胞的表面抗原[31] 在B淋巴细胞上表达[32] 肺癌
组织[33]PD-L1 同上 同上 PD-1 在活化的T细胞中诱导的抑制性受体[34] 活化的T、自然杀伤和B淋巴细胞、巨噬细胞、
树突状细胞和单核细胞上表达[35]CD8 细胞毒性T淋巴细胞标志物[36] 所有细胞毒性T淋巴细胞或杀伤细胞上[36] FoxP3 调节性T细胞的标志性分子[37] 调节性T细胞和正常上皮细胞及多种肿瘤细胞中[37] CD68 同上 同上 CK 同上 同上 头颈癌
组织[38]PD-1 同上 同上 OX40 免疫调节蛋白，主要由T细胞表达[39] 活化的CD4+和CD8+上表达、T细胞上表达以及
许多其他淋巴和非淋巴细胞[39]FoxP3 同上 同上 CD3 T细胞标志物[40] 存在于T细胞表面[40] 乳腺癌
组织[41]CD103 肿瘤浸润调节性T细胞的标志[42] 肠道粘膜上皮内的T细胞群和肠固有层白细胞上表达[42] CD8 同上 同上 
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表 2 全景数字病理设备产品主要参数
Table 2. The main parameters of panoramic digital pathology equipments
公司 型号 成像模式 切片容量 视场 成像速度 Zeiss Axio Scan.Z1 明场，荧光，偏振（选配） 12或100片（选配） 15 mm × 15 mm 20×明场：240 s/片；
荧光：NAAxioscan 7 明场，荧光，偏振（选配） 100片 10 mm ×10 mm 20×明场：73 s/片
20×荧光：（4通道）：323 s/片（ps: non-available, NA）
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