Th1 polarization in the tumor microenvironment upregulates the myeloid-derived suppressor-like function of macrophages
Kenichi Nonaka, Masanao Saio, Naoki Umemura, Arizumi Kikuchi, Takao Takahashi, Shinji Osada, Kazuhiro Yoshida
Abstract
Here, we investigated the effect of Th1 polarization in the tumor microenvironment (TME) on tumor-associated macrophage (TAM) maturation and activation. In our immunotherapy mouse model, with a Th1-dominant TME, tumors regressed in all cases, with complete regression in 80% of the cases. Monocyte-derived dendritic cells and activated CD4+ and CD8+ T-cells increased in the tumor-draining lymph node, and correlated with each other in the therapeutic model. However, the cytotoxicity of tumor-infiltrating CD8+ T-cells was slightly inhibited, whereas the number of T-cells significantly increased. Moreover, the number of TAMs increased; their maturation was inhibited; and nitrotyrosine (NT) production, as well as iNOS and arginase I expression, was increased, suggestive of the myeloid-derived suppressor cell-like immunosuppressive function of TAMs. IFN-γ knockout in the therapeutic model decreased NT production and induced macrophage maturation. Hence, Th1 polarization in the IFN-γ-dominant condition induces T-cell immune responses; however, it also enhances the immunosuppressive activity of TAMs.