课题基金基金详情
甲基化核蛋白p90aDMA在PD-L1抗体治疗乳腺癌中的作用和机制
结题报告
批准号:
81602700
项目类别:
青年科学基金项目
资助金额:
17.0 万元
负责人:
曹雪蕾
依托单位:
学科分类:
H1819.肿瘤生物治疗
结题年份:
2019
批准年份:
2016
项目状态:
已结题
项目参与者:
傅善基、阚士锋、魏守娟、李培龙、任浩
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
客服二维码
微信扫码咨询
中文摘要
针对PD-1/PD-L1信号通路设计的抗体治疗恶性肿瘤疗效显著,包括黑色素瘤、肺癌和乳腺癌等。大量研究表明,PD-1/PD-L1疗法能重塑肿瘤免疫微环境,但是其重塑的肿瘤微环境中细胞因子对于非对称性甲基化aDMA或对称性甲基化sDMA的调节及其效应机制尚未有所报道。我们在前期研究中发现, IL-2/4/6能特异性诱导p90aDMA高表达在乳腺癌细胞系的细胞核中。本课题拟通过建立4T1-PD-L1-/-小鼠肿瘤模型和PD-L1抗体治疗肿瘤模型以及细胞实验,揭示PD-L1抗体治疗导致的肿瘤免疫微环境下精氨酸甲基化信号通路的发生、效应和分子机制。本课题不仅对于阐明免疫细胞和肿瘤细胞之间通过细胞因子和转录后修饰介导的调控网络具有重要的理论价值,而且为临床应用PD-L1抗体治疗乳腺癌的疗效监测和预后提供分子靶标。
英文摘要
Immune checkpoint antibodies that augment the programmed cell death protein 1 (PD-1)/PD-L1 pathway have demonstrated antitumor activity across multiple malignancies including metastatic malignant melanoma, nonsmall-cell lung cancer and breast cancer. Recent researches show that the PD-1/PD-L1 therapies can re-educate the tumor environment (TME). Currently, the regulation and fuctions of aDMA or sDMA by cytokines in the tumor microenvironment reprogramed by PD-L1 antibodies remains largely unknown. Here we show that p90aDMA, p70aDMA, p90sDMA and p70sDMA were widely and dominantly expressed in breast cancer cell lines. Notably, it was p90aDMA rather than p90sDMA that accumulated in the nucleus upon stimulation of MDA-MB-231 cells with interleukin (IL)-2, IL-4 or IL-6. Our results raise the fundamental question of how IL-2/IL-4/IL-6 regulates the biogenesis of p90aDMA and whether aDMA takes place in the cytoplasm or the nucleus of breast cancer cells. Accumulating evidence is showing that breast cancer cells engage in novel associations / interdependencies with reprogrammed immune environment via methylation signals that may provide crucial contributions to promotion or suppression of antitumor PD-L1 antibodies immune response. To solve the above scientific hypotheses, a mouse 4T1 PD-L1 knockout (PD-L1-/-) tumor model mimicking PD-L1 therapies has been constructed for deeper research on molecular mechanisms involved in functions and regulation of methylation signals in re-educated TME by PD-L1 antibodies. This research will provide potential target of new therapies of cancer by PD-L1 antibody.
专著列表
科研奖励列表
会议论文列表
专利列表
国内基金
海外基金