Regulation of cell death and antitumor immunity by a natural triterpenoid in malignant lymphoma (TUM4P.930)

Abstract

Abstract B-cell lymphoma is a leading cause of hematological malignancies, accounting for almost 10% of new cancer-related deaths in the United States. In this study, we report that Ganoderic acid A (GA-A), a natural triterpenoid from the medicinal mushroom Ganoderma lucidum, induces anti-proliferative activity and apoptotic cell death in human B-cell lymphoma lines and primary B-cell tumors. GA-A treatment induced caspase-dependent apoptotic cell death characterized by a dose-dependent increase in active caspases 9 and 3, up-regulation of pro-apoptotic Bim and Bax proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA-A’s anti-growth activity, we show that lower doses of GA-A enhance HLA class II-mediated antigen presentation and CD4+ T cell recognition of lymphoma in vitro. The therapeutic relevance of GA-A treatment was tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA-A-treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked reduction of myeloid-derived suppressor cells (MDSC) in the host. Thus, GA-A not only selectively induces apoptosis in tumor cells, but also enhances cell-mediated immune responses by reducing MDSC and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA-A is a candidate for future drug design for the treatment of lymphoma.