Interferon-γ reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages

Tumor-associated macrophages (TAM) are M2d-polarized cells (IL-10(high), IL-12(low), ILT3(high), CD86(low)) that accumulate in tumor microenvironment. TAM inhibit antitumor T lymphocyte generation and function, contribute to tumor tolerance and are trophic for tumors. In this study, we investigated whether some immunological factors may reverse TAM immunosuppressive properties. Among 32 cytokines, we have identified IFN gamma on its ability to switch immunosuppressive TAM into immunostimulatory jells. Upon IFN gamma exposure, TAM purified from ovarian cancer ascites recover a M1 phenotype (IL-10(low), IL-12(high)), express high levels of CD86 and low levels of ILT3, enhance the proliferation of CD4(+) T lymphocytes and potentiate the cytotoxic properties of a MelanA-specific CD8(+) T cell clone. IFN gamma-treated TAM also secreted reduced levels of mediators promoting suppressive T cell accumulation (CCL18) and trophic for tumors (VEGF and MMP9). As TAM derive from the local differentiation of peripheral blood monocytes, we investigated whether IFN gamma may also affect TAM generation. In the presence of ovarian ascites, IFN gamma skewed monocyte differentiation from TAM-like cells to M1-polarized immunostimulatory macrophages. Together, these data show that IFN gamma overcomes TAM-induced immunosuppression by preventing TAM generation and functions. These data highlight that IFN gamma used locally at the tumor site could potentiate the efficacy of antitumor immunotherapies based on the generation of effector T cells. (C) 2009 UICC