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多靶点全景数字病理:从原理到应用

张新华 李才伟 张瑜 黄胜男 石晗 吴俊楠 任仕杰 刘珂含 高彤璐 史冰

张新华, 李才伟, 张瑜, 黄胜男, 石晗, 吴俊楠, 任仕杰, 刘珂含, 高彤璐, 史冰. 多靶点全景数字病理:从原理到应用[J]. 中国光学(中英文). doi: 10.37188/CO.2022-0091
引用本文: 张新华, 李才伟, 张瑜, 黄胜男, 石晗, 吴俊楠, 任仕杰, 刘珂含, 高彤璐, 史冰. 多靶点全景数字病理:从原理到应用[J]. 中国光学(中英文). doi: 10.37188/CO.2022-0091
ZHANG Xin-hua, LI Caiwei, ZHANG Yu, HUANG Shengnan, SHI Han, WU Junnan, REN Shijie, LIU Kehan, GAO Tonglu, SHI Bing. Multi-Target panoramic digital pathology: from principle to application[J]. Chinese Optics. doi: 10.37188/CO.2022-0091
Citation: ZHANG Xin-hua, LI Caiwei, ZHANG Yu, HUANG Shengnan, SHI Han, WU Junnan, REN Shijie, LIU Kehan, GAO Tonglu, SHI Bing. Multi-Target panoramic digital pathology: from principle to application[J]. Chinese Optics. doi: 10.37188/CO.2022-0091

多靶点全景数字病理:从原理到应用

doi: 10.37188/CO.2022-0091
基金项目: 国家自然科学基金地区项目(No. 82160345),海南省重点研发项目(No. ZDYF2021GXJS017),海口市重点科技计划项目(No. 2011-016),海南省自然科学基金(No. 620RC558)
详细信息
    作者简介:

    张新华(1995—),女,河南安阳人,博士研究生;2021年于海南大学获得硕士学位,主要从事图像处理方面的研究。E-mail:xinhuazhang@hainanu.edu.cn

    史 冰(1991—),女,吉林白城人,博士,讲师;2014年于长春理工大学获得学士学位,2021年于中国科学院大学获得博士学位,主要从事微流控液滴分析及临床细胞、组织样本的快速检测分析研究。E-mail:shibing@hainanu.edu.cn

  • 中图分类号: TP394.1;TH691.9

Multi-Target panoramic digital pathology: from principle to application

Funds: Supported by Key research and development program of Hainan province (No. ZDYF2021GXJS017),National Natural Science Foundation of China (No. 82160345),Key science and technology plan project of Haikou (No. 2011-016),Hainan Provincial Natural Science Foundation of China (No. 620RC558)
More Information
  • 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,在确保分辨率的前提下,无法兼顾全景成像。全景数字病理的提出,弥补了这一缺陷,在保证分辨率的同时兼顾了全景成像。但单张切片仅能实现单靶点的检测,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的巨大的应用潜力而广受关注。其系统凭借视场大、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的技术的更新迭代,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三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现状。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。

     

  • 图 1  常规免疫组织化学实验流程

    Figure 1.  Conventional immunohistochemistry staining procedures

    图 2  基于TSA的多重荧光免疫组化流程

    Figure 2.  Multiplex fluorescent immunohistochemistry based on TSA

    图 3  光谱成像示意图[68](F:滤光片;BS:分光镜;M1/M2/M3:反射镜;P:色散棱镜)

    Figure 3.  Spectral imaging diagram[68] (F: filter; BS: beam splitter; M1/M2/M3: mirror; P: dispersive prism)

    图 4  面扫描和线扫描[79]

    Figure 4.  Area scan and line scan [79]

    图 5  Olympus VS200 研究级全玻片扫描系统[83]

    Figure 5.  Olympus VS200 Research Slide Scanner[83]

    图 6  全景数字病理图像拼接流程

    Figure 6.  Mosaic process of panoramic digital pathological images

    图 7  肿瘤微环境[106]

    Figure 7.  Tumor microenvironment[106]

    图 8  三级淋巴结构免疫标记荧光成像[106]

    Figure 8.  Immunolabeling fluorescence imaging of tertiary lymphoid structures[106]

    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[21]
    CK一种细胞角蛋白,是上皮来源的肿瘤标志物[22]主要在上皮细胞中表达的中间丝蛋白[22]
    CD68巨噬细胞标记物[23]存在于骨髓和神经的吞噬细胞[24]
    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[21]
    骨髓细胞,人类癌细胞和肿瘤浸润性骨髓细胞[21]
    肝癌
    组织[25]
    PD-L1对抗PD-1/PD-L1治疗反应的预测性生物标志物[26]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[26]
    CD68同上同上
    CD33髓系细胞分化抗原[27]主要分布在髓系血细胞[27]
    CD57人类自然杀伤细胞标记物[28]人类自然杀伤细胞和T淋巴细胞[28]
    CD11b粘附分子和介导多种配体识别的膜受体[29]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[29]
    CD20B细胞的表面抗原[30]在B淋巴细胞上表达[31]
    肺癌
    组织[32]
    PD-L1同上同上
    PD-1在活化的T细胞中诱导的抑制性受体[33]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[34]
    CD8细胞毒性T淋巴细胞标志物[35]所有细胞毒性T淋巴细胞或杀伤细胞上[35]
    FoxP3调节性T细胞的标志性分子[36]调节性T细胞和正常上皮细胞及多种肿瘤细胞中[36]
    CD68同上同上
    CK同上同上
    头颈癌
    组织[37]
    PD-1同上同上
    OX40免疫调节蛋白,主要由T细胞表达[38]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[38]
    FoxP3同上同上
    CD3T细胞标志物[39]存在于T细胞表面[39]
    乳腺癌
    组织[40]
    CD103肿瘤浸润调节性T细胞的标志[41]肠道粘膜上皮内的T细胞群和肠固有层白细胞上表达[41]
    CD8同上同上
    下载: 导出CSV

    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 equipment products

    公司型号成像模式切片容量视场成像速度
    ZeissAxio Scan.Z1明场,荧光,偏振(选配)12或100片(选配)15 mm × 15 mm20×明场:240 s/片
    荧光:NA
    Axioscan 7明场,荧光,偏振(选配)100片10 mm ×10 mm20×明场:73 s/片
    20×荧光:(4通道):323 s/片
    (ps: non-available, NA)
    下载: 导出CSV
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