Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. The tumor immune microenvironment (TIME) formed by interactions among cancer cells, immune cells, cancer-associated fibroblasts (CAF), and extracellular matrix (ECM) components drives PDAC in a more immunosuppressive direction: this is a major cause of therapy resistance and poor prognosis. In recent years, research has advanced our understanding of the signaling mechanism by which TIME components interact with the tumor and the evolution of immunophenotyping. Through revolutionary technologies such as single-cell sequencing, we have gone from simply classifying PDACs as "cold" and "hot" to a more comprehensive approach of immunophenotyping that considers all the cells and matrix components. This is key to improving the clinical efficacy of PDAC treatments. In this review, we elaborate on various TIME components in PDAC, the signaling mechanisms underlying their interactions, and the latest research into PDAC immunophenotyping. A deep understanding of these network interactions will contribute to the effective combination of TIME-based therapeutic approaches, such as immune checkpoint inhibitors (ICI), adoptive cell therapy, therapies targeting myeloid cells, CAF reprogramming, and stromal normalization. By selecting the appropriate integrated therapies based on precise immunophenotyping, significant advances in the future treatment of PDAC are possible.

Bufalin inhibits TGF-ß-induced epithelial-to-mesenchymal transition and migration in human lung cancer A549 cells by downregulating TGF-ß receptors.

The epithelial-to-mesenchymal transition (EMT) is a well-known prerequisite for cancer cells to acquire the migratory and invasive capacity, and to subsequently metastasize. Bufalin is one of the major active components of the traditional Chinese medicine Chan Su, and accumulating evidence has shown its anticancer effect in multipe types of cancer. However, the role of bufalin in transforming growth factor­ß (TGF­ß)­induced EMT and migration remains unclear. In the present study, the effect of bufalin on TGF­ß­induced EMT and migration was investigated in human lung cancer A549 cells. TGF­ß induced EMT in A549 cells and increased their migratory ability, which were markedly suppressed by bufalin. Additionally, TGF­ß­induced upregulation of Twist2 and zinc finger E­box binding homeobox 2 (ZEB2), as well as the phosphorylation of Smad2 and Smad3 were also inhibited by bufalin. However, the Smad­independent signaling pathways were not affected. Further analysis showed that the TGF­ß receptor I (TßRI) and TGF­ß receptor II (TßRII) were downregulated in the presence of bufalin. Pretreatment with SB431542, a potent inhibitor of the phosphorylation of TßRI, significantly attenuated TGF­ß­induced EMT, mimicking the effect of bufalin on A549 cells. Taken together, these results suggest that bufalin suppresses TGF-ß-induced EMT and migration by downregulating TßRI and TßRII in A549 cells.

Treatment of allergic inflammation and hyperresponsiveness by a simple compound, Bavachinin, isolated from Chinese herbs.

Asthmatic inflammation is mediated by a type 2 helper T cell (Th2) cytokine response, and blocking Th2 cytokine production is proven to have a potent therapeutic effect against asthmatic inflammation. Using IL-4-green fluorescent protein (GFP) reporter mice, we demonstrated that Bavachinin, a single compound isolated from a Chinese herb, significantly inhibited Th2 cytokine production, including IL-4, IL-5 and IL-13. Notably, this compound almost completely blocked inflammation in the ovalbumin (OVA)-sensitized animal asthma model. Furthermore, we demonstrated that this chemical selectively affects the level of GATA-3, most likely by affecting the stability of GATA-3 mRNA. Our results demonstrate, for the first time, the potential therapeutic value of this single compound derived from Chinese herbs.