中药斑蝥素衍生物LB-100联合顺铂阻断肿瘤微环境中免疫抑制效应提高恶性胸膜间皮瘤疗效的机制研究

恶性胸膜间皮瘤具有高度侵袭性、预后较差；实体瘤中新型的化疗结合免疫治疗的关键优势在于能打破肿瘤微环境的免疫抑制作用。前期研究发现中药斑蝥素衍生物LB-100能够影响肿瘤微环境中T细胞分化及巨噬细胞极化，而恶性胸膜间皮瘤组织中CD8+效应T细胞数量与预后呈正相关。因此我们提出假说LB-100通过调节肿瘤浸润免疫细胞的分化提高疗效。本项目拟采用大鼠肿瘤模型，结合临床样本，首先明确恶性胸膜间皮瘤中普遍存在免疫抑制微环境，探索顺铂联合LB-100抑制肿瘤浸润免疫细胞的蛋白磷酸酶2A（PP2A）活性的作用，进而研究通过调控PP2A/mTOR通路促进效应T细胞分化及PP2A/NLRP3通路介导炎症小体失活阻断肿瘤相关巨噬细胞M2型极化的效应，阐明化疗联合现代中药单体在恶性胸膜间皮瘤中重塑肿瘤免疫微环境的分子机制。该研究有望为补充中医学扶正祛邪治则及抗肿瘤免疫中药衍生物的开发提供理论依据。

Malignant pleural mesothelioma is highly invasive with a poor prognosis in intrathoracic malignancies. Now chemotherapy combined with immunotherapy in solid cancer shows great therapeutic advantages that breaking the immunosuppression in tumor microenvironment. In the previous study, it was found that the cantharidin derivative LB-100 can regulate T cell differentiation and macrophage polarization in tumor microenvironment, meanwhile the increased infiltrated numbers of CD8+ effector T cells in malignant pleural mesothelioma showed a favorable prognosis. Therefore, we hypothesized that LB-100 can improve the treatment efficacy by inducing differentiation and activating tumor infiltrated effector T cells. This project intends to use the rat orthotopic tumor model combined with clinical tumor samples to confirm the presence of immunosuppressive microenvironment in malignant pleural mesothelioma. Then we would explore the effect of LB-100 combined with cisplatin on tumor infiltration of immune cells through inhibiting serine/threonine protease phosphatase 2A (PP2A). Furthermore, the molecular mechanisms related with the differentiation of effector T cells induced by PP2A/mTOR pathway and activation of effector T cell regulated by inhibiting M2-type macrophages polarization through PP2A/NLRP3 inflammasomes disassembling would be studied. Our results that the remodeling effect of chemotherapy combined with Chinese herbal on tumor immune microenvironment and improvements of anti-malignant pleural mesothelioma treatment are supposed to provide a theoretical basis for the development of tumor immunomodulatory drugs from derivatives in traditional Chinese medicine and therapeutics of Chinese medicine.