运动可调节肺癌小鼠模型中肿瘤相关巨噬细胞的极化及相关免疫检查点的表达。
Exercise modulates polarization of TAMs and expression of related immune checkpoints in mice with lung cancer.
作者信息
Ge Zhe, Wu Shan, Qi Zhengtang, Ding Shuzhe
机构信息
School of Sport, Shenzhen University, Shenzhen 518060, China.
Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China.
出版信息
J Cancer. 2022 Sep 6;13(12):3297-3307. doi: 10.7150/jca.76136. eCollection 2022.
Many studies have found that both endurance exercise (EX) and high-intensity interval training (HIIT) have a positive therapeutic effect on the treatment of lung cancer patients, but the specific mechanism is unclear. Therefore, we investigated whether EX and HIIT could delay the progression of lung cancer by affecting the infiltration of tumor-associated macrophages (TAMs) and restoring the tumor phagocytic activity of TAMs in lung cancer tissue. BALB/c mice were divided into 4 groups. The mice were given saline as the saline group (Saline), and the mice were given urethane as the lung cancer mice. The lung cancer mice were randomly divided into the control group (CON), EX group, and HIIT group. After exercise, the cancer tissues were collected for RT-PCR, immunofluorescence staining, and Wes automated western blotting system analysis. Compared with the Saline group, the mRNA levels of TAMs M1 markers IL-6, TNF-α, iNOS, and M2 markers CD206, IL-10, and Arg-1 in the CON group were significantly increased (P<0.05). There was no significant difference in the percentage of F4/80 positive cells among the groups. Compared with the CON group, the percentage of CD86-positive cells in TAMs in the EX group was significantly decreased (P<0.05). From the protein expression level, compared with the CON group, the expression of SIRPα in the EX group was significantly increased (P<0.0001) and the expression of PD-L1 had a tendency to increase (P=0.06). Compared with the CON group, the expressions of IL-10, IL-12, CD47, and CD24 in the HIIT group were significantly increased (P<0.05). In addition, compared with the CON group, plasma IFN-γ in the EX group and HIIT group was significantly increased (P<0.05). Lung cancer tissue presents an inflammatory tumor microenvironment. The therapeutic effect of exercise on lung cancer is independent of the infiltration of TAMs in lung cancer tissue. In addition, endurance exercise can reduce the proportion of M1-type TAMs in lung cancer tissues, while HIIT antagonistically regulates M1 and M2 polarization of TAMs by increasing the levels of IL-10 and IL-12 in lung cancer tissues and circulating IFN-γ. Finally, endurance exercise and HIIT can modulate the expression of some immune checkpoints in lung cancer tissues.
许多研究发现,耐力运动(EX)和高强度间歇训练(HIIT)对肺癌患者的治疗均具有积极的治疗效果,但具体机制尚不清楚。因此,我们研究了EX和HIIT是否可以通过影响肿瘤相关巨噬细胞(TAM)的浸润并恢复肺癌组织中TAM的肿瘤吞噬活性来延缓肺癌的进展。将BALB/c小鼠分为4组。给小鼠注射生理盐水作为生理盐水组(Saline),给小鼠注射乌拉坦作为肺癌小鼠。将肺癌小鼠随机分为对照组(CON)、EX组和HIIT组。运动后,收集癌组织进行RT-PCR、免疫荧光染色和Wes自动蛋白质免疫印迹系统分析。与Saline组相比,CON组中TAM的M1标志物IL-6、TNF-α、iNOS以及M2标志物CD206、IL-10和Arg-1的mRNA水平显著升高(P<0.05)。各组间F4/80阳性细胞百分比无显著差异。与CON组相比,EX组中TAM中CD86阳性细胞的百分比显著降低(P<0.05)。从蛋白质表达水平来看,与CON组相比,EX组中SIRPα的表达显著增加(P<0.0001),PD-L1的表达有增加趋势(P=0.06)。与CON组相比,HIIT组中IL-10、IL-12、CD47和CD24的表达显著增加(P<0.05)。此外,与CON组相比,EX组和HIIT组的血浆IFN-γ显著增加(P<0.05)。肺癌组织呈现出炎性肿瘤微环境。运动对肺癌的治疗效果与肺癌组织中TAM的浸润无关。此外,耐力运动可降低肺癌组织中M1型TAM的比例,而HIIT通过增加肺癌组织中IL-10和IL-12的水平以及循环IFN-γ来拮抗调节TAM的M1和M2极化。最后,耐力运动和HIIT可调节肺癌组织中一些免疫检查点的表达。
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