基于“金水相生”理论探讨非小细胞肺癌化疗微环境中IL-7/ IL-7R信号通路的响应及益气养阴填髓方的干预作用

Tumor microenvironment is closely related to the development of chemotherapy resistance. Previous study found that Yiqi Yangyin Tiansui recipe based on the mutual promotion between lung and kidney can protect the bone marrow suppression after chemotherapy, enhance immune regulation function, and strengthen the anti-tumor effect of cisplatin. Further study found that this recipe can up-regulate serum and tumor levels of IL-7, and induce IL-7R expression in tumor tissue. Therefore, we speculate that its anti-tumor effect is associated with tumor microenvironment improvement. We propose the following hypothesis: Yiqi Yangyin Tiansui recipe can enhance cisplatin susceptibility by inducing immune cell activation, improving tumor microenvironment, and activating IL-7/IL-7R-mediated signaling pathway. In this study, we will establish a model of lung cancer with deficiency of qi and yin and detect the effect of this recipe on the type and number of regulatory T cell subsets to determine its regulation of tumor microenvironment in vivo.IL-7 / IL-7R-mediated signaling pathways and protein expression levels of drug-resistant genes were verified in vivo and in vivo experiments to demonstrate the above hypothesis. The mechanism of the mutual promotion between lung and kidney in the treatment of lung cancer was established by studying the curve of dose-effect relationship, calculating the dose-effect relationship. This study will provide a scientific basis for finding drugs and treatments for sensitization and reversal of drug resistance in non-small cell lung cancer chemotherapy.

肿瘤微环境与非小细胞肺癌化疗耐药的发生发展关系密切。前期研究发现，基于“金水相生”的益气养阴填髓方能保护化疗后骨髓抑制，提高免疫调节功能，并能增强顺铂抗肿瘤作用。进一步研究发现该方能上调血清和瘤体中IL-7的水平，并诱导瘤组织中IL-7R的表达。因此，我们推测其抗肿瘤作用与改善肿瘤微环境有关，提出“益气养阴填髓方通过诱导免疫细胞活化，改善肿瘤微环境，并激活IL-7/IL-7R介导的信号通路以增强顺铂药敏性”假说。本课题将构建气阴两虚型肺癌小鼠模型，通过检测该方对调节性T细胞亚群类型和数量的影响，确定其在体内对肿瘤微环境的调节作用；通过检测体内外实验中IL-7/IL-7R介导的信号通路以及耐药基因的表达水平以论证上述假说；并通过对其剂量-效应关系进行研究，计算量效关系曲线模型以确证“金水相生法”在肺癌治疗中的作用机理，为找到针对非小细胞肺癌化疗起到增敏及逆转耐药的药物和治疗方法提供科学依据。

肿瘤微环境与非小细胞肺癌化疗耐药的发生发展关系密切。前期研究发现，基于“金水相生”的益气养阴填髓方能保护化疗后骨髓抑制，提高免疫调节功能，并能增强顺铂抗肿瘤作用。进一步研究发现该方能上调血清和瘤体中IL-7的水平，并诱导瘤组织中IL-7R的表达。因此，我们推测其抗肿瘤作用与改善肿瘤微环境有关，提出“益气养阴填髓方通过诱导免疫细胞活化，改善肿瘤微环境，并激活IL-7/IL-7R介导的信号通路以增强顺铂药敏性”假说。于是，本课题通过体内外实验观察益气养阴填髓方对肺癌化疗药敏性的影响。一方面，先通过体内实验，检测外周血中Tregs亚群的类型以及数量，确定该方在体内对肿瘤免疫微环境的调节作用。然后，进行体外细胞实验，确定该方在体外通过IL-7/IL-7R介导的信号通路促进肺癌细胞化疗药敏的作用机制；另一方面，我们发现，IL-7可通过IL-7R-JAK3/STAT5信号通路促进NSCLC细胞对顺铂的敏感性。IL-7通过抑制 ABCG2 使非小细胞肺癌对顺铂重新敏感。从而更充分阐明了益气养阴填髓方通过IL-7/IL-7R介导信号通路促进肺癌细胞化疗药敏的作用机制，揭示“金水相生法”在肺癌化疗中的作用机理。