AIM2调控肿瘤相关巨噬细胞极化影响肾癌进展的作用机制研究

Tumor associated macrophages (TAMs) are divided into M1 and M2 subpopulation, its infiltration and polarization play a critical role in tumor progression. Increasing evidences indicate that absent in melanoma 2 (AIM2) is involved in the inflammation responses. In the preliminary study, the expression of AIM2 was reduced in TAMs of renal carcinoma tissues, and it was negatively correlated with the TAMs infiltration or M2 polarization; In vitro, renal carcinoma cells could induce the decreased expression of AIM2 and M2 polarization in macrophages. Over-expression of AIM2 in macrophages changed the macrophage polarization from M2 to M1, accompanied by the reduced infiltration, migration or proliferation of renal carcinoma cells, suggesting that AIM2 may modulate macrophage polarization in renal carcinoma microenvironment. In this proposal, we would like to explore the molecular mechanisms of AIM2-mediated macrophage polarization in renal carcinoma, including: ① The correlation between the expression of AIM2 in TAMs of renal carcinoma tissues and the infiltration or polarization of TAMs; ② The role of AIM2-mediated macrophage polarization in the development of renal carcinoma cells in vitro; ③ The role of macrophage polarization modulated by AIM2 in renal carcinoma model; ④ The mechanism of macrophage polarization modulated by AIM2 in renal carcinoma. Our studies will provide new mechanisms of TAMs polarization and TAMs target for treatment of renal carcinoma or other tumors.

肿瘤相关巨噬细胞（TAMs）包括巨噬细胞M1和M2两种亚群，其浸润和极化是肿瘤进展的重要因素之一。已有研究证实，黑色素瘤缺乏因子2（AIM2）与炎症反应密切相关。申请者前期实验发现，肾癌组织TAMs 的AIM2表达下调，且与TAMs的浸润及M2极化呈显著负相关；体外肾癌细胞能诱导巨噬细胞M2型极化并下调AIM2的表达；巨噬细胞过表达AIM2后，其极化表型由M2向M1转变，并抑制肾癌细胞的迁移、侵袭和增殖，表明AIM2与TAMs的极化密切相关。本项目拟对AIM2调控TAMs极化影响肾癌进展的作用机制进行研究，包括：①肾癌组织TAMs的AIM2表达与TAMs浸润与极化关系；②AIM2调控巨噬细胞极化对肾癌细胞的作用；③AIM2调控TAMs极化影响肾癌进展的作用；④AIM2 调控TAMs极化的机制。本研究将加深TAMs极化机制的理解，为肾癌或其它肿瘤的TAMs靶标治疗提供新的靶点与途径。

肿瘤相关巨噬细胞（TAMs）包括巨噬细胞M1和M2两种亚群，其浸润和极化是肿瘤进展的重要因素之一。已有研究证实，黑色素瘤缺乏因子2（AIM2）与炎症反应密切相关。申请者前期实验发现，肾癌组织TAMs 的AIM2表达下调，且与TAMs的浸润及M2极化呈显著负相关；体外肾癌细胞能诱导巨噬细胞M2型极化并下调AIM2的表达；巨噬细胞过表达AIM2后，其极化表型由M2向M1转变，并抑制肾癌细胞的迁移、侵袭和增殖，表明AIM2与TAMs的极化密切相关。利用过表达AIM2的巨噬细胞进行过继转移治疗后，显著抑制小鼠肾癌皮下瘤与肺转移瘤的生长，并伴随肿瘤组织M1巨噬细胞浸润增加，M2细胞浸润减少。给予炎性体抑制剂的处理，废除了过表达AIM2巨噬细胞对肾癌细胞的杀伤及肿瘤生长的抑制。这些结果表明过表达AIM2促进巨噬细胞极化是依赖于炎性体信号激活途径，从而介导调控巨噬细胞极化对肾癌细胞的杀伤作用；因此，本研究加深TAMs了极化机制的理解，为肾癌或其它肿瘤的TAMs靶标治疗提供了新的靶点与途径。