肿瘤浸润Treg调控TAMs型别转换在Lewis肺癌侵袭与转移中的作用研究

Invasion-metastasis cascade represents the primary cause for death of cancer patient. More than 90% of mortality from cancer is attributable to metastases. Thus, our ability to effectively treat cancer is largely dependent on our capacity to interdict the process. Accumulating evidence unambiguously show that metastasis requires close collaboration between cancer cells, immune and inflammatory cells. It will be great importance to clarify the role of the transition of TAMs from M1 type to M2 type on tumor invasion and metastasis. However, the functional significance of TAMs transition on tumor invasion and metastasis in the lung cancer remains poorly understood. For this reason, Lewis cancer mouse model of lung metastasis will be utilized in the present study. Firstly, we shall evaluate the role of TAMs transition in the tumor invasion and metastasis and identify the biological features of transited TAMs during this process. Secondly,by using in vivo depletion of Treg in WT bearing mice and adoptive transfer of Treg to nude mice. we shall clarify the regulatory role of Treg on TAMs transition and its impact to tumor invasion and metastasis. Furthermore, by co-culture of Treg purified from tumor microenvironment with TAMs and/or tumor organoids,we shall also indentify the characteristics of transited TAMs orchestrated by Treg and explor the relative mechanism that underlies the critical role of Treg regulating the transition of M1 to M2 in the tumor invasion and metastasis. RANK signaling controls osteoclastogenesis and bone resorption and has been targeted to prevent bon metastasis in breast and prostate cancer. Emerging evidence has shown that RANKL expressed by Treg also play crucial role in pulmonary metastasis of breast cancer. Thus, finally, by using intratumoral administration of RANKL and/or its decoy receptor, OPG, we shall thoroughly illustrate the dependence of pulmonary metastasis on Treg will be replaceable of RANKL, which stimulate metastasis through instruction of the transition of M2 cells. The current study will elucidate a novel mechanism that there are possible positive feedback loop between TAMs transition and Treg regulation, transited M2 cells induced Treg activation and conversely, activated Treg cells promote the transition of TAMs to M2 cells, which utmatelly related to tumor invasion and metastasis cascade and highlight the potential for prevention and therapy.

恶性肿瘤严重威胁人类健康，而肿瘤转移又是大多数患者的死因。研究发现，肿瘤细胞的侵袭和转移与炎症、免疫应答密切相关，如肿瘤微环境中巨噬细胞（TAMs）的型别转换在这一过程中的作用就备受关注。研究TAMs型别转换的生物学特点、调控机制及其在肿瘤侵袭与转移中的作用将为恶性肿瘤的免疫防治提供新思路。本项目组前期工作提示，TAMs型别转换与调节型T细胞（Treg）呈现负相关。拟利用Lewis肺癌转移模型，研究Treg诱导的TAMs型别转换在恶性肿瘤侵袭与转移的作用；通过在荷瘤小鼠体内清除Treg，过继回输Treg等实验，结合体外组织细胞共培养、瘤内注射等实验系统分析Treg调控与TAMs型别转换的关系并探讨相关机制；以期丰富肿瘤免疫学知识，为相关疾病的免疫防治提供理论和实验依据。