Therapeutic targeting of tumor associated macrophages.

Previous studies on the mechanistic induction of anti-tumor responses by IL-12 cytokine therapy have focused on the adaptive immune response, specifically the activation NK cells and T cells as the primary targets of IL-12 treatment. In contrast, little attention has been given to the potential role of macrophages in the initiation of anti-tumor responses by IL-12 therapy despite reports that macrophages play a major role in promoting tumor growth and metastasis and in suppressing anti-tumor immune responses. Based on the functional adaptivity hypothesis, which is the concept that macrophages functionally adapt, rather than differentiate into specific mature subsets, in response to environmental stimuli, we hypothesized that tumor infiltrating (TIMs) as well as tumor-associated macrophages (TAMs) could be converted from tumor supportive activities to pro-immunogenic activities by IL-12 therapy. We examined the functional activities displayed by TIMs and TAMs after treatment with IL-12. Our data demonstrate (1) that tumor cells and tumor exosomes activate TIMs and TAMs by cell-contact dependent mechanisms involving ligation of CD40 and/or NKG2D, (2) that IL-12 treatment both in vivo and in vitro induces a rapid reduction of tumor supportive activities and a concomitant increase in pro-inflammatory activities in TIMs as well as TAMs, (3) that IL-12 induces a rapid release of cytoplasmic IL-I5 from the in situ activated tumor associated macrophages and (4) the release of IL-15 in essential to the recruitment of lymphocytes to the tumor and the metastatic lung, and to the destruction of the tumor and clearance of metastasis. It is concluded that macrophages in the tumor environment are activated and functionally modulated by the tumor. TIMs and TAMs respond to IL-12 treatment by rapidly converting from suppressive, tumor supportive activities to inflammatory, pro-immunogenic activities. Tumor associated macrophages thus are a critical target of IL-12 therapy and may orchestrate the subsequent NK and T cell cytotoxic response against the tumor.