Anti-tumor immune responses of tumor-associated macrophages via toll-like receptor 4 triggered by cationic polymers

Abstract

Agonists of toll-like receptors (TLRs) are potential therapeutic reagents for cancer immunotherapy. Cationic polymers such as polyethyleneimine (PEI) with nucleic acid drug delivery capability are approved for use in clinical trials, and recent reports indicate that these cationic polymers have significant immunological activity mediated by TLRs. In the present study, we demonstrated that cationic polymers such as PEI and cationic dextran could reverse tumor-associated macrophages (TAMs) polarization and promote IL-12 expression both in vitro and in vivo. The stimulatory role of cationic polymers was remarkably attenuated in TAMs pre-treated with TLR-4 blocking antibody or TAMs from TLR-4 knockout mice. Additionally, these cationic polymers exerted direct tumoricidal activity by promoting Th 1 and NK cell infiltration, suppressing tumor angiogenesis and prolonging the survival of sarcoma-bearing wild-type. These phenomena were abrogated in TLR-4 knockout mice, suggesting that the immune stimulation was primarily mediated by TLR-4. In conclusion, these results demonstrated that cationic polymers could transform the immunotolerogenic phenotype of TAMs through TLR-4 signaling, thereby promoting therapeutic anti-tumor immunity. Our present study suggests a new class of drugs as a candidate for future cancer immunotherapy.