Xiao Xiaoqian, Li Yanping, Wang Yi, Zhang Yuxi, Chen Jilan, Liu Weiwei, Tang Jingyi, Yue Fuping, Yang Jiahui
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Int Immunopharmacol. 2022 Feb;103:108427. doi: 10.1016/j.intimp.2021.108427. Epub 2021 Dec 15.
Preclinical and clinical data show a close relationship between high infiltration of tumor-associated macrophages (TAMs) and a poor prognosis in most types of tumors, thus targeting TAMs stands out as promising anticancer immunotherapies. Recent studies have demonstrated the anti-tumor effects of artemisinin via enhancing anti-tumor immunity within tumor microenvironment, but the underlying mechanism is still not clear. In the present study we uncovered an important role of dihydroartemisinin (DHA) in regulating intratumoral TAM polarization and anti-tumor immune responses in mouse Lewis Lung carcinoma model. We found that DHA inhibited Lewis Lung carcinoma progress, moderately decreased the frequencies of TAMs within tumor stroma, and significantly increased CD86 expression while decreased CD206 expression on TAMs which indicates the role of DHA in polarizing TAMs into a M1-like phenotype. Then, our in vitro data confirmed that DHA dose-dependently promoted macrophage M1 phenotype transition by increasing M1 phenotype-related molecules, meanwhile decreasing the expression of M2 phenotype-related molecules. In addition, DHA increased proinflammatory cytokine production, enhanced the phagocytic capacity while decreased anti-inflammatory cytokine production. Finally, in order to prove that AKT/mTOR signaling potentially mediated DHA-induced macrophage differentiation, we used rapamycin to specifically block the activity of mTOR and stimulated macrophages under M1 stimuli. Our data clearly showed that rapamycin significantly decreased DHA-induced M1-related phenotypes and proinflammatory cytokine expression. In summary, our study highlighted DHA as one of future potential therapeutic options for the development of novel anticancer immunotherapies in lung cancer.
临床前和临床数据表明，在大多数类型的肿瘤中，肿瘤相关巨噬细胞（TAM）的高浸润与预后不良密切相关，因此靶向TAM成为有前景的抗癌免疫疗法。最近的研究表明青蒿素通过增强肿瘤微环境中的抗肿瘤免疫发挥抗肿瘤作用，但其潜在机制仍不清楚。在本研究中，我们在小鼠Lewis肺癌模型中发现了双氢青蒿素（DHA）在调节肿瘤内TAM极化和抗肿瘤免疫反应中的重要作用。我们发现DHA抑制Lewis肺癌进展，适度降低肿瘤基质中TAM的频率，并显著增加TAM上CD86的表达，同时降低CD206的表达，这表明DHA在将TAM极化为M1样表型中的作用。然后，我们的体外数据证实，DHA通过增加M1表型相关分子，同时降低M2表型相关分子的表达，剂量依赖性地促进巨噬细胞向M1表型转变。此外，DHA增加促炎细胞因子的产生，增强吞噬能力，同时降低抗炎细胞因子的产生。最后，为了证明AKT/mTOR信号可能介导DHA诱导的巨噬细胞分化，我们使用雷帕霉素特异性阻断mTOR的活性，并在M1刺激下刺激巨噬细胞。我们的数据清楚地表明，雷帕霉素显著降低了DHA诱导的M1相关表型和促炎细胞因子的表达。总之，我们的研究强调了DHA作为未来肺癌新型抗癌免疫疗法开发的潜在治疗选择之一。
