Kiyota Tsuyoshi, Takahashi Yuki, Watcharanurak Kanitta, Nishikawa Makiya, Ohara Saori, Ando Mitsuru, Watanabe Yoshihiko, Takakura Yoshinobu
Department of Biopharmaceutics and Drug Metabolism and ‡Department of Molecular Microbiology, Graduate School of Pharmaceutical Science, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
Mol Pharm. 2014 May 5;11(5):1542-9. doi: 10.1021/mp4007216. Epub 2014 Apr 7.
Tumor-associated macrophages (TAMs) negatively affect the therapeutic effects of anticancer agents. To examine the role of TAMs in interferon (IFN)-γ gene therapy, we selected two types of solid tumors, which varied in the number of TAMs, and investigated the effects of IFN-γ gene transfer on tumor growth. Many TAMs were detected in the solid tumors of murine adenocarcinoma colon-26 cells, whereas few TAMs were detected in murine melanoma B16-BL6 cells. IFN-γ gene transfer hardly suppressed the growth of colon-26 tumors, whereas it was effective in suppressing the growth of B16-BL6 tumors. The antiproliferative effects of IFN-γ on cultured colon-26 cells were similar to those on cultured B16-BL6 cells. To evaluate the role of TAMs, we injected clodronate liposomes (CLs) modified with poly(ethylene glycol) (PEG) to functionally deplete TAMs in tumor-bearing mice. Repeated injections of PEG-CLs significantly retarded the growth of colon-26 tumors and combination with IFN-γ gene transfer further inhibited the growth. In contrast, PEG-CLs hardly retarded the growth of B16-BL6 tumors. These results clearly indicate that TAM depletion is effective in enhancing the therapeutic effect of IFN-γ in TAM-repleted and IFN-γ-resistant tumors.
