免疫卡控点B7-H1、B7-H3和B7-H4病理检测试剂的研制及其在肠癌组织多重染色分析的临床意义
结题报告
批准号:
31700778
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
黄子逸
依托单位:
学科分类:
C0805.肿瘤免疫微环境
结题年份:
2020
批准年份:
2017
项目状态:
已结题
项目参与者:
郭凌川、曹磊、古彦铮、丁思思、安竞男、李小平
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中文摘要
肿瘤微环境中异常表达的免疫卡控点B7-H1、B7-H3和B7-H4等是参与肿瘤免疫逃逸的关键分子,但其在肿瘤演进中的表达规律及涉及的关键细胞和机制尚待进一步探讨。我们自主研制了系列抗人B7-H1、B7-H3和B7-H4单抗,发现B7-H1、B7-H3在结直肠息肉阶段表达上调,B7-H4仅在癌变阶段表达,且表达与浸润免疫细胞相关。鉴此,本项目(1)对已获得的B7-H1、B7-H3和B7-H4免疫组化抗体进一步鉴定,按临床病理诊断试剂要求建立质控参数;(2)建立新型的免疫组化多重染色方法,实现结直肠癌组织中3种分子的精确定位;(3)利用特异性单抗动态分析上述分子在人结直肠正常和癌变组织的表达规律及其与浸润免疫细胞的相关性和可能的调控机制。本研究不仅为免疫卡控点治疗提供伴随诊断试剂,还通过多重染色对人结直肠癌演进组织进行动态分析,为疾病免疫评价提供多参数指标,有助于阐明肿瘤免疫逃逸的机制。
英文摘要
Recently, we found that B7-H1(PD-L1), B7-H3 and B7-H4 were highly expressed in colorectal cancer tissues and showed differential expression levels during disease progression. B7-H1, B7-H3 and B7-H4 expression in colorectal cancer tissues can be heterogeneous in staining intensity and have variable distribution throughout an individual tissue. We have succeeded in developing anti-human B7-H1, B7-H3 and B7-H4 mAbs suitable for immunohistochemical staining in formalin-fixed tissue sections with reliable clarity and intensity. The purpose of the project is to apply multiplex immunohistochemistry and objective assessment parameters to identify B7-H1, B7-H3 and B7-H4 that correlate with colorectal cancer status, T cell infiltrate, and patient survival. B7-H1, B7-H3 and B7-H4 monoclonal antibodies were developed for IHC detection providing a consistent and objective assessment for tumor diagnosis and prognosis on a multi-analysis basis. Three-color IHC detection will be used in a single tissue sample with B7-H1, B7-H3 and B7-H4 monoclonal antibodies achieving a high level of sensitivity and specificity. We will systematically determine the expression pattern of B7-H1, B7-H3 and B7-H4 molecules at different stages of colorectal cancer and its correlation with immune cell subsets in tumor microenvironment, as well as clinic pathological parameters. Relationships analysis among B7-H1, B7-H3, B7-H4, CD8+ TILs and macrophage will be performed to examine the dynamic interactions that occur within the tumor microenvironment, which could be significant to determine the immune classification (immunoscore) in cancer patients. These mAbs are potentially useful as companion diagnostic agents to analyze B7-H1, B7-H3 and B7-H4 expression in the clinical setting while the expression pattern in the corresponding stage will be important to clarify tumor immune escape mechanism at different stages of colorectal cancer.
肿瘤发展过程中逐步建立的免疫抑制微环境,有利于肿瘤细胞生长和肿瘤免疫逃逸,最终进展成为临床癌症。PD-L1、B7-H3和B7-H4在肿瘤组织的表达与微环境中免疫细胞(CD8+TIL、CD68+巨噬细胞、Treg)的相关性研究是肿瘤免疫逃逸和肿瘤预后评估的重要因素,本项目(1)研制了系列特异性抗人PD-L1(B7-H1)、B7-H3、B7-H4、CD8和CD68免疫组化检测抗体,分析系列免疫控卡点分子PD-L1、B7-H3、B7-H4结肠癌演进不同阶段微环境表达规律及可能的作用机制;(2)获得了肿瘤类型特定、细胞染色特异的PD-L1免疫组化抗体,有助于开发肿瘤个体化用药的PD-L1检测产品,促进PD-L1 IHC检测抗体和病理评分的标准化和规范化;(3)建立了抗体的体外表达工艺,进一步提高抗体表达量,优化培养过程中的物理条件如温度、pH、营养成分等各参数指标,形成抗体、质控的稳定性工艺。本项目具有一定的运用研究和临床转化价值。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Evaluation of the role of B7-H3 haplotype in association with impaired B7-H3 expression and protection against type 1 diabetes in Chinese Han population
中国汉族人群中 B7-H3 单倍型与 B7-H3 表达受损及预防 1 型糖尿病相关的作用评估
DOI:10.1186/s12902-020-00592-7
发表时间:2020
期刊:BMC Endocrine Disorders
影响因子:2.7
作者:Ding Sisi;Shan Yimei;Sun Lili;Li Sicheng;Jiang Rong;Chang Xin;Huang Ziyi;Sun Jing;Liu Cuiping;Fang Chen;Zhang Xueguang
通讯作者:Zhang Xueguang
DOI:10.13312/j.issn.1671-7783.y190008
发表时间:2019
期刊:江苏大学学报(医学版)
影响因子:--
作者:黄子逸;陈晨;彭雪楠;申春苹;朱一蓓;王雪峰;张学光
通讯作者:张学光
DOI:10.1111/jcmm.14082
发表时间:2019
期刊:JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
影响因子:5.3
作者:Wang Yuhong;Hu Lin;Zheng Yushuang;Guo Lingchuan
通讯作者:Guo Lingchuan
国内基金
海外基金