Administration of both IL-2 and Soluble form TNF receptor type II inhibits maturation and infiltration of tumor associated macrophages in liver implantation model of colon cancer Free

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Introduction: Tumor associated macrophage (TAM) have killing activity mediated by both nitric oxide (NO) and tumor necrosis factor-α (TNF) against tumor cells. However, NO and TNF produced by macrophages are responsible for immunosuppression due to suppressing proliferation and activity of cytotoxic lymphocyte. We reviewed the remedy of administration both IL-2 and soluble form TNF receptor type II (sTNFRII) focusing on role of TAM. Methods: In order to simulate the remedy, vector vehicle alone, sTNFRII, IL-2, or combination of IL-2 and sTNFRII (double) were introduced into murine colon cancer (MCA 38). We made the sole metastatic colon cancer model by inoculating cancer cells to C57BL/6 mouse liver directly. Twelve days after the inoculation, tumors were collected and analyzed. Results: Both MCA/mock and MCA/sTNFRII did not have repressive effect on tumor growth. MCA/IL-2 had repressive effect on approximately 60% of mice inoculated. While, MCA/double showed strong regression and almost tumors were rejected. Sizes of tumor were correlated with the maturation of TAMs. Furthermore, NO productions of TAMs stimulated by IFN-γ were correlated with the maturation of TAMs as well. On western blotting, amounts of inducible NO synthase (iNOS) in freshly prepared TAMs which mediate NO production, were very little on each TAM group. In addition, no significant difference between each group was noted. However, amount of arginase on TAM which competes for L-arginine with iNOS, and is expressed as the M2 macrophage, was significantly expressed in “double” group. After stimulation by IFN-g, GAPDH of “double” group TAM was almost disappeared. That is, much TAM collected from “double” group had died after the incubation. However, the one recovered from gld mice were reluctant to die after 24hrs incubation. Conclusions: According to the present interpretation of TAM polarization, TAM in “double” group seemed to be tilted to M2 dominant, which will inhibit immune response. However, the most important thing we have to focus on is decreased infiltration and inhibited maturation of TAM in “double” group. Our data suggested that inhibition of TAM maturation and infiltration would released the other immune cells from inhibitory effect of TAM, that is, small number of TAM M2 polarization seemed not to inhibit anti-tumor immune response.