No abstract

The efficacy of cancer immunotherapy is limited by immunosuppression in the tumor microenvironment. Regulatory T cells (Treg) are found at high frequency in tumors, and have greater suppressive activity than Treg from spleen or lymph node tissues. In addition, IL-10 limits the activation of antigen presenting cells and production of proinflammatory cytokines at the tumor site. We examined the cellular sources of IL-10 in the tumor. Using IL-10GFP (VERTX) reporter mice and real-time PCR assays, IL-10 expression was detected in Ly6C+ myeloid cells, macrophages and approximately 50% of tumor Tregs. A similar portion of tumor Treg produced IL-10 following stimulation with PMA/ionomycin. Microarray analyses on IL-10 positive and IL-10 negative tumor Treg and total spleen Treg revealed an activation signature associated with IL-10 expression. This signature correlated strongly with expression of the transcription factor Maf and with induction a type I IFN/STAT1-signature. Using knockout mice we observed that both the type I IFN receptor, IFNAR1 and STAT1 were required for normal tumor Treg frequencies and IL-10 production. This indicates that the STAT1/IFNAR1 axis is required to drive immunosuppressive Treg and their production of IL-10 in the tumor microenvironment. Therefore the immunostimulatory effects of type I IFN are paralleled with an increase in Treg function and IFNAR1/STAT1 may constitute an important therapeutic target for tumor Treg.