ABSTRACT
Though the importance of IFN-gamma in tumor immunity has been well-demonstrated, little is known about its source and how it is induced. By using various bone marrow chimeric mice, we show here that IFN-gamma essential for tumor immunity is solely produced by hemopoietic cells. Surprisingly, IFN-gamma derived from T cells was not necessary for tumor immunity in this model. In the immunized mice, in which only innate immune cells have the IFN-gamma-producing potential, tumors were efficiently rejected. The innate immune cells, such as NK1.1(+) cells and CD11b(+) cells, can provide sufficient amounts of IFN-gamma which requires, however, the help of T cells. The close cooperation between T cells and innate immune cells during tumor regression is likely mediated by IL-2. Together, our results clearly illustrate how T cells cooperate with innate immune cells for IFN-gamma-mediated tumor rejection and this may have important indications for clinical trials of tumor immunotherapy.
Subject(s)
Bone Marrow Cells/immunology , Cell Communication/immunology , Graft Rejection/immunology , Graft Rejection/pathology , Immunity, Innate , Interferon-gamma/physiology , T-Lymphocytes/immunology , Adoptive Transfer , Animals , Antigens, Ly , Antigens, Surface/biosynthesis , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , CD11b Antigen/biosynthesis , Cell Communication/genetics , Cell Line, Tumor , Graft Rejection/genetics , Immunity, Innate/genetics , Interferon-gamma/deficiency , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-2/physiology , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lectins, C-Type/biosynthesis , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , NK Cell Lectin-Like Receptor Subfamily B , Neoplasms, Experimental/genetics , Neoplasms, Experimental/immunology , Neoplasms, Experimental/prevention & control , Radiation Chimera , T-Lymphocytes/metabolism , T-Lymphocytes/transplantationABSTRACT
It is thought that tumor rejection by CD8(+) T-cell effectors is primarily mediated by direct killing. We show that rejection of different tumors (fibrosarcoma, ras-transformed fibroblasts, colon carcinoma, and plasmacytoma) by CD8(+) T cells is always preceded by inhibition of tumor-induced angiogenesis. Angiostasis and tumor rejection were observed in perforin but not in IFN-gamma-deficient mice. Furthermore, adoptive transfer of tumor-specific CD8(+) T cells from IFN-gamma-competent mice inhibited angiogenesis of lung metastases in comparison to those from IFN-gamma gene-deficient mice. Taken together with our previous findings, we conclude that IFN-gamma-dependent antiangiogenesis is a general mechanism involved in tumor rejection by CD4(+) and CD8(+) T-cell effectors.
