中国被毛孢菌粉通过Notch信号调控乳腺癌肿瘤微环境T细胞亚群的分子机制研究

肿瘤微环境效应T细胞比例直接决定肿瘤命运。扶正固本干预肿瘤免疫微环境在中医抗肿瘤中具有重要地位。预实验数据显示虫草菌粉（中国被毛孢，HSM）不仅能抑制乳腺癌，还能促进T细胞激活及其Notch 受体mRNA表达。据此提出假设:HSM通过Notch信号调控乳腺癌微环境T细胞亚群的抗肿瘤模式。我们将依托Lck Cre Notch1f/f PyMT、Lck Cre Notch1f/f OT1 等多种转基因小鼠模型,深入研究条件性Notch1敲除PyMT小鼠遗传表型和肿瘤微环境T细胞亚群特点;系统评价HSM抗肿瘤作用及对T细胞激活,增殖和功能影响。在此基础上进一步通过iTRAQ定量蛋白组及全转录组表达谱芯片技术,阐明Notch信号在肿瘤微环境中T细胞亚群分化机制,明确HSM抗肿瘤免疫分子机制。通过该研究我们将建立一套较完备的肿瘤免疫研究体系,为今后开发中药肿瘤免疫治疗药物奠定基础。

Proportion of cytotoxic T cells in tumor microenvironment directly determines tumor fate. Tumor microenvironment interfering with the principle of reinforcing the vital energy and consolidating the constitution has an important position among anti-tumor with Chinese medicine. Our preliminary experimental data showed that Hiresutella sinensis mycelium (HSM) not only inhibited tumor growth, but also promoted T cell activation and induced T cell Notch receptor mRNA expression. So we hypothesized that HSM inhibits tumor growth by regulating the breast tumor microenvironment T cell activation through Notch signaling. We will study genetic phenotypes of conditional Notch1-ko PyMT mice and the characteristics of the tumor microenvironment of T cell subgroup using multiple transgenic mouse model, such as Lck Cre Notch1f/f PyMT mice and Lck Cre Notch1f/f OT1 mice; and evaluate the anti-tumor activity and the effects on T cell activation, proliferation and function of HSM. On this basis, to explore Notch signaling involved in the differentiation mechanism of T cell subsets by iTRAQ quantitative proteomics technology and the transcriptome expression profile chip technology, and clarify the molecular mechanism of anti-tumor immunity activation of HSM. We will establish a more complete tumor immunity technology research platform for the further development of traditional Chinese medicine for cancer immunotherapy drugs in the future.