Th1 polarization in the tumor microenvironment upregulates the myeloid-derived suppressor-like function of macrophages

[Display omitted] •IFN-γ in Th1-dominant TMEs activates tumor-infiltrating macrophages.•Combined IL-2 and sTNFRII promotes the Th1 polarization of TDLN T-cells and TILs.•Combined IL-2 and sTNFRII increases MoDC and cDC population in draining lymph nodes.•Combined IL-2, sTNFRII and peroxynitrate inhibitor may improve immunotherapy. 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.