CCL2-CCR2轴调控TAMs免疫逃逸介导乳腺癌大分割放射治疗后肿瘤复发及机制研究

大分割放射治疗是乳腺癌重要局部治疗方式，仍有部分患者出现对放疗不敏感甚至复发，是目前临床亟待解决的重要问题。而目前大分割放疗后肿瘤复发的具体机制尚不明晰。我们前期研究发现：大分割放疗后分泌高水平CCL2趋化肿瘤相关巨噬细胞(TAMs)与乳腺癌放疗后复发有着密切联系。基于此我们设想：大分割放疗激活CCL2-CCR2轴募集TAMs向肿瘤浸润，分泌VEGF从而触发放疗后血管再生，并且抑制CD8+T细胞浸润及细胞毒作用，从而导致肿瘤复发。本课题拟通过体外细胞共培养及荷瘤小鼠模型从分子、细胞、组织水平上来探讨大分割放疗后CCL2-CCR2轴募集TAMs与肿瘤复发之间关系，探究大分割放疗后CCL2-CCR2轴对于TAMs调控作用，明确TAMs通过重塑肿瘤微血管及肿瘤免疫逃逸微环境对肿瘤放疗后复发起着重要作用，为阐明肿瘤大分割放疗后肿瘤局部复发机制、提高放疗局控、探索潜在治疗靶点提供新的视野和理论依据。

Hypofractionated radiotherapy is an important local treatment for breast cancer, but some patients still have suffered with radiation resistance even tumor relapse, which is considered as a tough issue to be solved urgently in clinical practice. At present, the specific mechanism of tumor recurrence after hypofractionated radiotherapy is not clear. Our previous study found that the secretion of high-level CCL2 induced tumor-related macrophages (TAMs) infiltration, which was closely associated with recurrence of breast cancer after hypofractionated radiotherapy. Based on these results, we put forward a hypothesis that hypofractionated radiotherapy activates the CCL2-CCR2 signaling axis recruiting TAMs infiltration to the tumor, secreting VEGF to trigger revascularization, and inhibiting the infiltration and cytotoxic effect of CD8+T cells, thus leading to tumor recurrence after hypofractionated radiotherapy. This project aims to explore the relationship between tumor recurrence and CCL2-CCR2 signaling axis recruiting TAMs , to investigate the molecular mechanisms of CCL2-CCR2 signaling axis modulating TAMs function and to reveal the vital role of TAMs in remodeling the tumor microvessel and immune evasive microenvironment which results in tumor recurrence after hypofractionated radiotherapy by established cell co-culture and tumor-burdened mouse models. Our study will offer a novel insight and lay a theoretical foundation for clarifying the mechanism of tumor recurrence of breast cancer after hypofractionated radiotherapy, improving local tumor control and developing potential therapeutic targets.