Tumor-Derived Cytokines Dysregulate Macrophage Interferon-γ Responsiveness and Interferon Regulatory Factor-8 Expression

Abstract

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 (MΦ) 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-γ-mediated activation pathways. The tumor-derived immunosuppressive cytokines interieukin-10 and transforming growth factor-β, constrain IRF-8 production by normal MΦs, regardless of priming, and IRF-8 is also dysregulated in primary MΦs from tumorburdened 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.