Macrophage functional plasticity: IL-12 rapidly alters the functional profile of tumor associated and tumor infiltrating macrophages in vivo. (50.4)

Abstract

Abstract Tumor-associated macrophages play a major role in promoting tumor growth and metastasis and in suppressing the anti-tumor immune response. Despite the immunosuppressive environment created by the tumor and enforced by tumor-associated macrophages, treatment of tumor-bearing mice with IL-12 induces tumor regression associated with appearance of activated NK cells and activated tumor-specific cytotoxic T cells. We therefore tested the hypothesis that IL-12 treatment could alter the function of these tumor-associated “suppressor” macrophages. Analysis of tumor infiltrating macrophages (TIMs) and distal tumor associated macrophages (TAMs) revealed that IL-12, both in vivo and in vitro, induced a rapid (< 90 min) reduction of tumor supportive macrophage activities (IL-10, MCP-1, MIF, TGFâ production) and a concomitant increase in pro-inflammatory and pro-immunogenic activities (TNFá, IL-15, IL-18 production). Similar shifts in functional phenotype were induced by IL-12 in TIMs isolated from the primary tumor mass and in TAMs isolated from lung containing metastases, spleen and peritoneal cavity. Therefore, although tumor associated macrophages display a strongly polarized immunosuppressive functional profile, they retain the ability to change their functional profile to pro-inflammatory activities given the appropriate stimulus. The ability of IL-12 to initiate this functional conversion may contribute to early amplification of the subsequent destructive anti-tumor immune response. This research was supported by the Nat’l Cancer Institute, the KY Lung Cancer Research Fdn, the American Lung Assoc., and the KY Research Challenge Trust Fund.