A TCM Formula YYWY Inhibits Tumor Growth in Non-Small Cell Lung Cancer and Enhances Immune-Response Through Facilitating the Maturation of Dendritic Cells

Abstract

In worldwide, lung cancer has a major socio-economic impact and is one of the most common causes of cancer-related deaths. Current therapies for lung cancer are still quite unsatisfactory, urging for alternative new treatments. Traditional Chinese Medicine (TCM) is currently increasingly popular and exhibits a complicated intervention in cancers therapy. In this study, we evaluated the anti-tumor effect and explored the mechanisms of a TCM formula Yangyinwenyang (YYWY) in non-small cell lung cancer (NSCLC) models. YYWY induced the apoptosis of lung cancer cells in vitro. In Lewis NSCLC-bearing mice model, YYWY significantly inhibited the tumor growth. Further, RNA-seq analysis and immunostaining of the tumor tissue implied the critical role of YYWY in the regulation of immune response, especially the dendritic cells (DCs) in the effect of YYWY. Therefore, we focused on DCs, which were the initiator and modulator of the immune response. YYWY facilitated the maturation of DCs through MAPK and NF-kB signaling pathways and promoted the release of the cytokines IFN-g, interleukin (IL)-1b, IL-2, IL-12, and tumor necrosis factor (TNF)-a by DCs. Moreover, the YYWY-matured DCs enhanced the proliferation of T cells and promoted the differentiation of T cells into T helper Th1 and cytotoxic T cell (CTL). In addition, YYWY increased the ratio of Th1/Th2 (IFN-g/IL-4 radio). Collectively, our findings clearly suggested that YYWY exerted an anti-tumor effect on NSCLC, at least partially through facilitating the mature DCs to activate the proliferation and differentiation of T cells.

Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions

“…The underlying mechanisms may lie in the effects of Tmod1 on the TLR4-mediated signaling pathways. Downstream of TLR4, the MyD88-dependent NF-κB and MAPK pathways control the expression of costimulatory molecules and proinflammatory cytokines ( 52 – 55 ). Western blotting data showed that compared to Tmod1 +/+ DCs, degradation of IκB was delayed and phosphorylation of p65 and p38 was reduced in TOT/Tmod1 -/- DCs under LPS stimulation ( Figures 3A, B ).…”

Large-Scale Transcriptome Analysis Identified a Novel Cancer Driver Genes Signature for Predicting the Prognostic of Patients With Hepatocellular Carcinoma

“…Our study also demonstrates the involvement of these immune functional assemblies and immune cells in the process of tumor mutagenesis, which may indirectly affect the survival prognosis of patients. Immune cell alterations such as dendritic cells and Th2 cells are important triggers of tumor immune infiltration and subsequent vascular invasion, and their activation also correlates with the patient's response to immune and biological vaccine therapy (Moreira et al, 2020;Patel et al, 2020;Zhao et al, 2020). HLA and CCR also affect various aspects of the body's immune system (Attia et al, 2020).…”

Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment

“…In addition, in H-22 tumor-bearing mice, YPF elevated the ratio of Th1/Th2 (IFN-g/ IL-4) through mature DCs, thus ameliorating Th2-biased immune state (12). Similarly, YYWY exerted the anti-tumor effect by inducing DCs mature, which subsequently activated CD4 + T lymphocytes and enhanced Th1 function (29). Chen et al found that in CT26 tumor-bearing mice, Quxie capsule (QX) intervention boosted the expression of Foxo1 and T-bet, along with the augment of Th1 and Th1/Th2, to propel the immune response in TME (44).…”

“…YYWY intervention drove the impregnation of DCs, CD4 + and CD8 + T cells in LLC tissues, and raised the mRNA levels of IFN-γ, IL-1β, TNF-α and IL-12. In addition, YYWY stimulated MAPK and NF-κB signaling pathways in bone marrow dendritic cells (BMDCs) to accelerate the maturation of DCs and the proliferation and differentiation of T cells together ( 29 ). TSLP, an immune-related factor, can activate DCs and involve in T cell differentiation, which raises the expression of Th2-polarizing molecule CD252 (OX40L), and induces Th2 response ( 42 ).…”

“…In addition, in H-22 tumor-bearing mice, YPF elevated the ratio of Th1/Th2 (IFN-γ/IL-4) through mature DCs, thus ameliorating Th2-biased immune state ( 12 ). Similarly, YYWY exerted the anti-tumor effect by inducing DCs mature, which subsequently activated CD4 + T lymphocytes and enhanced Th1 function ( 29 ). Chen et al.…”