自噬对化疗药物诱导的白血病细胞抗肿瘤免疫效应的作用及机制研究

The abnormality of immunogenic cell death is the most important reason of leukemia resistant to chemotherapy, and become one of the hot topics in cancer therapy. Our previous studies have demonstrated that autophagy is an important factor of leukemia cells resistant to chemotherapy. Related studies have shown that autophagy can regulate myeloid leukemia cell differentiation, also participate in the endoplasmic reticulum stress as well as innate immune response. Based on these findings we hypothesize that autophagy has an impact on leukemia cells resistant to chemotherapy through mediating immunogenic cell death. We will examine the effect of autophagy on calreticulin translocation, ATP release, chaperone expression, DCs maturation and T cell immune activation in leukemia cells at the molecular, cellular and whole animal level, and the possible molecular mechanisms and signaling pathways. Our aim is to further characterize the mechanisms of autophagy between the tumor cell death and immune system activation, and the determinants of tumor escape with the long-term goal of, provided new ideas and experimental clues for leukemia immunotherapy, which is important for translation medicine.

免疫原性细胞死亡的异常是白血病对化疗耐药的重要原因，是目前肿瘤治疗中的重点之一。本人及项目组前期在《leukemia》《autophagy》等期刊上报道了自噬是白血病细胞化疗耐药的重要原因，自噬可以调控髓系白血病细胞分化，相关研究也表明自噬可参与内质网应激反应以及固有免疫反应。在此基础上我们提出“自噬可能通过调控免疫原性细胞死亡，从而对白血病细胞化疗耐药产生影响”的科学假说，在分子、细胞和整体动物水平，探讨自噬对白血病细胞钙网蛋白转位、ATP释放、分子伴侣表达、DCs活化及T细胞免疫的影响，并初步探讨其可能分子机制及信号通路。其中自噬调控信号通路是研究重点。开展本项目可望揭示自噬在死亡肿瘤细胞与免疫体系活化之间的作用，揭示肿瘤细胞死亡逃逸的决定因素，为白血病免疫治疗开辟新的思路与实验线索。

白血病化疗耐药是目前白血病治疗中的重点之一。前期项目组提出通过影响自噬可以调控免疫原性细胞死亡，从而对白血病细胞化疗耐药产生影响。项目组通过多种检测方法发现抑制自噬能够影响白血病细胞免疫原性细胞死亡中代表性的钙网蛋白转位、分子伴侣表达，但对关键性的DCs活化及T细胞免疫的影响却与预期不一致。同时发现分子或基因水平抑制自噬能明显减弱白血病细胞糖酵解水平，减少肿瘤细胞能量供应从而提高化疗敏感性，其中LDHA可能是多种白血病细胞糖酵解的共同干预靶点。本项目的完成可能为白血病靶向治疗和药物开发提供新的思路。