Abstract 4708: Anti-tumor phenotype of tumor-associated macrophages are induced by COX-2 inhibition via the up-regulation of IFN-γ.

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Abstract BACKGROUNDS AND AIMS Macrophages are a major constituent in tumor stroma, and macrophages infiltrating tumors are called tumor-associated macrophages (TAMs). Macrophages have a functional plasticity depending on the stimuli from microenvironment. M1 macrophages are induced by Th1 cytokines, and exerted anti-tumor function. On the contrary, M2 macrophages are induced by Th2 cytokines, and showed pro-tumor phenotype. TAMs are considered to shift from M1 to M2 during tumor progression. However, the mechanism for this M1/M2 switch is poorly understood. Cyclooxygenase-2 (COX-2)/PGE2 pathway is up-regulated in a variety of cancers including colorectal cancers, and promotes the cancer progression. COX-2 inhibition shows anti-tumor effect in familial adenomatous polyposis patients and in Apc knockout mice. Although COX-2 inhibition affects cytokine expression profiles and tumor microenvironments, the relationship between COX-2/PGE2 pathway and TAM phenotypes remains unclear. The aim of this study is to uncover the effects of COX-2 inhibition on TAM phenotypes and cytokine expression. METHODS Cytokine expression and the phenotypes of TAMs infiltrating the stroma of ApcMin/+ mouse polyps were examined by qRT-PCR and immunohistochemistry in terms of M1 and M2 dichotomy. Selective COX-2 inhibitor was administered to ApcMin/+ mice, and the effects of COX-2 inhibition on cytokine expression and TAM phenotypes were evaluated. Furthermore, by using mouse peritoneal macrophages, the direct effects of COX-2 inhibitor on Th1- or Th2-related cytokines on macrophage phenotypes were examined. RESULTS Th2 cytokines were predominant in ApcMin/+ mouse polyps, and TAMs were polarized to M2. Selective COX-2 inhibitor skewed TAM phenotypes from M2 to M1, accompanied by tumor regression in ApcMin/+ mice. Concomitantly, the expression of M1-related cytokine IFN-γ was significantly up-regulated by COX-2 inhibition, although that of M2-related cytokines IL-4, IL-13, and IL-10 was not significantly altered. Administration of COX-2 inhibitor alone was insufficient to alter the phenotypes of mouse peritoneal macrophages from M2 to M1. However, IFN-γ treatment polarized the macrophage phenotypes from M2 to M1 even in the presence of M2-related cytokines IL-4, IL-13, and IL10. CONCLUSIONS Our results suggest that COX-2 inhibition induced anti-tumor (M1) phenotype of TAMs via the up-regulation of IFN-γ, and subsequently, may suppress intestinal tumor progression in ApcMin/+ mouse polyps. Citation Format: Yuki Nakanishi, Masato Nakatsuji, Hiroshi Seno, Tsutomu Chiba. Anti-tumor phenotype of tumor-associated macrophages are induced by COX-2 inhibition via the up-regulation of IFN-γ. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4708. doi:10.1158/1538-7445.AM2013-4708