Study of fumagillin analogues on murine immune cells and immunomodulatory effects in different cancer models

Abstract

Fumagillin is the natural product isolated from fungus Aspergillus fumigatus, and is recognized as a potent anti-angiogenic compound. Substantial investigation has been focused on the anti-tumor activities of fumagillin and its analogues, some of which have been adopted in pre-clinical and clinical studies. However, investigation on the immunomodulating activities of this class of compounds is limited and results have been controversial. As there is intense interest in elucidating the interrelation between immune modulation and tumor development, novel immunopharmacological properties of chemotherapeutic agents have recently been explored for their therapeutic potentials in clinical applications. As a combination to both these research topics, fumagillin and its synthetic analogues were firstly investigated on different types of immune cells, such as T lymphocytes, dendritic cells and macrophages. F23, a fumagillin analogue with potent immunological activities, was further examined in three different murine cancer models, EL4 lymphoma, CT26 colon carcinoma and 4T1 mammary carcinoma, and their anti-tumor activities and intrinsic immunomodulatory effects were explored. Fumagillin and its analogues exert diversified functions in different types of immune cells. For example, they showed inhibitory effects on cell proliferation and cytokine production of T lymphocytes upon polyclonal stimulation, stimulatory effects on dendritic cells by inducing a highly-matured population, which contributed to induction of syngeneic and allogeneic lymphocyte proliferation and a preference to Th1 polarization, and multiple effects on macrophages based on phenotypic and cytokine analyses. Studies in murine cancer models showed that the fumagillin analogue F23 caused substantial inhibition of tumor development in three cancer models to different extents, with pronounced inhibitory effects on the expansion and functions of myeloid-derived suppressor cells (MDSCs), the signature cell population responsible for tumor progression and refractoriness to chemotherapeutic and immunotherapeutic agents, thereby suggesting the novel immunopharmacological properties of fumagillin and its analogues contributed to tumor suppression.