Abstract
Yu-Ping-Feng (YPF) formula is a classical prescription used for enhancing the body's immunity function in traditional Chinese medicine (TCM). In clinical practice, the YPF formula has been reported to exhibit antilung cancer and immunomodulatory effect. However, the relationship between them remains unclear. The present study aimed to investigate the antilung cancer effect of the YPF formula and its immune-related mechanisms. The C57BL/6 tumor-bearing mice model was established and randomly divided into the YPF group and the control group. Tumor volume, spleen weight, and survival in both groups were measured and evaluated during 28 days of consecutive intervention. Flow cytometry was used to detect the proportion of immune cell subsets. Myeloid-derived suppressor cells (MDSCs) were induced in vitro from bone marrow cells. After intervention by the YPF formula, CCK-8 and flow cytometry analyses were performed to detect proliferation and apoptosis of MDSCs. A coculture system containing T cells and MDSCs was established to further study the role of MDSCs in the regulation of T-cell subsets proportion by the YPF formula. The expressions of MDSCs-related genes and proteins were detected by RT-PCR and Western blotting. The results showed the YPF formula inhibited tumor growth, reduced spleen weight, and prolonged the survival of mice. Besides, the proportions of MDSCs subsets and Regulatory T (Treg) in the YPF group decreased, whereas those of CD4+T and CD8+T increased both in vitro and in vivo. CCK-8 and flow cytometry demonstrated that the YPF formula could inhibit proliferation and promote apoptosis of MDSCs. The coculture experiments further confirmed that MDSCs served a critical role in regulating the tumor microenvironment by the YPF formula. RT-PCR and Western blotting indicated that the levels of MDSCs' activation and proliferation-related proteins and genes were downregulated in the YPF group. Therefore, our results demonstrated that the YPF formula could promote apoptosis and inhibit the proliferation of MDSCs. As a result, the negative regulatory effect on the positive immune cells induced by MDSCs was weakened, thus achieving the antilung cancer effect by remodeling the tumor microenvironment.
Highlights
Lung cancer is the leading cause of cancer morbidity and mortality worldwide [1]
Related research demonstrated that Treg cells were significantly increased in acute myeloid leukemia (AML), and downregulating the level of CD25+FOXP3+Treg cells in the tumor microenvironment (TME) contributed to clinical benefit in patients with refractory AML
For T-cell subsets, the proportions of CD4+T and CD8+T in the YPF group increased, whereas the proportion of Treg decreased significantly in the YPF group, as shown in Figures 2 and 3. ese results indicated that the YPF formula could positively regulate the immune response of tumorbearing mice, which was manifested as a decrease in the proportion of negative immune cells (MDSCs subsets and Tregs), as well as an increase in the proportion of positive immune cells (CD4+ and CD8+T cells) in the tumor microenvironment
Summary
Lung cancer is the leading cause of cancer morbidity and mortality worldwide [1]. In China, according to relevant statistical results, there were about 787,000 new cases of lung cancer and about 631,000 deaths resulting from lung cancer [2]. Previous research demonstrated that large infiltration of MDSCs in the TME was closely related to the poor prognosis of lung cancer [11]. Us, targeting the phenotype and function of MDSCs in the TME may be one of the potential treatment strategies for lung cancer [12]. MDSCs, as one of the most important immune suppressive cells in the TME, possess complex phenotypes. MDSCs could promote the polarization of macrophages toward the M2 phenotype and form into tumor-associated macrophages (TAMs) with negative immune regulatory effects [18]. E YPF formula is a classical TCM prescription that was invented by Zhu Danxi during the Ming Dynasty of China. A clinical study showed that the YPF formula could improve the immune function and the life quality of lung cancer patients undergoing chemotherapy [24]. Since there is proven antitumor effect of the YPF formula in our previous studies and its immunomodulatory effect [25], we try to elucidate the potential antilung cancer mechanism of the YPF formula from the perspective of modulating the tumor immune microenvironment
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