Antitumor Immunity Induced by Irradiated Tumor Cells Producing Macrophage Colony-Stimulating Factor
Kagawa University, Takamatu, Kagawa, JapanInternational Journal of Hematology (Impact Factor: 1.92). 05/2001; 73(3):378-82. DOI: 10.1007/BF02981965
We previously reported that administration into mice of mouse lymphoid leukemia L1210 cells engineered to secrete macrophage colony-stimulating factor (M-CSF) could lead to tumor rejection. Here, we demonstrate that inoculation with irradiated M-CSF-producing cells protects mice against a subsequent challenge with unmodified parental tumor cells. We used 2 experimental protocols: the inoculation with irradiated M-CSF-producing L1210 cells (EM5) before the challenge with parental cells and after the challenge with parental cells. Both protocols effectively improved the survival rate of mice compared with protocols in which irradiated non-M-CSF-producing L1210 cells (EM-mock) were inoculated. Inoculation with 1 x 10(2) irradiated EM5 cells was sufficient to prolong the survival time of mice subsequently challenged with 1 x 10(4) parental cells. In vivo depletion experiments with administration of antibodies suggested the involvement of CD4+ T cells, CD8+ T cells, and natural killer (NK) cells in the antitumor effect. Consistent with these findings, the cytotoxic T lymphocyte activity of splenocytes from EM5-inoculated mice was higher than that from EM-mock-inoculated mice, and L1210 tumors were heavily infiltrated by CD4+ T cells and NK cells as well as macrophages in EM5-inoculated mice.
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ABSTRACT: Homeostasis-driven proliferation of T cells is an important means of reconstituting T-cell-dependent immunity after lymphodepletion regimens, such as chemotherapy or radiotherapy. Immune-reconstituted mice that receive a tumor vaccine mount more efficient anti-tumor immune responses compared with control mice. In the present study, we evaluated the anti-tumor immune responses in immune-reconstituted mice vaccinated with inactivated leukemia cells and explored the mechanisms underlying these immune responses. Test C57BL/6 mice were lymphodepleted by irradiation and immune-reconstituted with naïve mouse spleen lymphocytes. Mice were then injected with an inactivated FBL-3 tumor cell vaccine and challenged with FBL-3 tumor cells. Anti-tumor responses were evaluated by determining the rate of tumor formation, latency, tumor size, interferon gamma levels, and macrophage and CTL cytotoxicities. When challenged with tumor cells, immune-reconstituted, vaccinated mice exhibited a significantly lower mortality, smaller average tumor volume, and a significantly longer mean survival time. They had more robust cellular immunity, reflected by higher levels of INF-γ production and higher macrophage- and CTL-mediated cytotoxicities. Our results suggest that immune reconstitution enhanced the anti-tumor immune responses in mice injected with a tumor vaccine via generation of CTLs. These results have important implications for immunotherapy used for leukemia.
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