Tumor-derived cytokines dysregulate macrophage interferon-gamma responsiveness and interferon regulatory factor-8 expression

Tumors can evade immune responses through suppressor signals that dysregulate host effector cell function. In this study we demonstrate that tumor-derived suppressor molecules impede host antitumor immune activity through dysregulation of multiple macrophage (Mphi) pathways, including suppressed production of cytotoxic and immunostimulatory agents and impaired expression of the interferon regulatory factor-8 (IRF-8) protein, a critical transducer of interferon-gamma-mediated activation pathways. The tumor-derived immunosuppressive cytokines interleukin-10 and transforming growth factor-beta(1) constrain IRF-8 production by normal Mphis, regardless of priming, and IRF-8 is also dysregulated in primary Mphis from tumor-burdened hosts. Collectively, these data describe a new mechanism by which tumors disrupt immune function and suggest that abrogation of tumor-derived immunoregulatory factors in situ can restore immune function and enhance antitumor efficacy.