| Abstract: |
Macrophage-derived chemokine is chemotactic for a variety of leukocytes, and has been shown to be involved in TH2-mediated cellular immunity. To evaluate the role of this chemokine in tumor immunity in vivo, an adenovirus vector encoding the human macrophage-derived chemokine cDNA (AdMDC) was administered to established murine tumors. Gene transfer with AdMDC significantly inhibited tumor growth and prolonged animal survival. AdMDC was not directly cytotoxic to tumor cells, but splenocytes from animals that received intratumoral AdMDC were able to lyse syngeneic tumor cells, and purified splenic CD8+ cells secreted interferon-γ in a tumor-specific manner. The antitumor activity of AdMDC was lost in mice lacking CD8+ T lymphocytes, but surprisingly, it was preserved in animals lacking CD4+ cells, as was the systemic cytotoxic T lymphocyte response. Systemic NK cells did not play a role in the antitumor immune response induced by AdMDC. Experiments using knockout mice demonstrated that host expression of MHC Class I, but not Class II, IL-4, or IL-12, was necessary for AdMDC to exert its antitumor effect, and immunohistochemistry demonstrated infiltrates of CD8+ and CD86+ cells, but not CD4+ cells in treated tumors. These studies highlight a new function for macrophage-derived chemokine by demonstrating that it possesses in vivo antitumor activity with CD8+ T cells as the effector cells, and interestingly, that the CD4+ cell/MHC II pathway of CD8+ cell activation is not required for the antitumor effects of this chemokine. |
| Keywords: |
immunohistochemistry; cancer survival; treatment outcome; survival rate; drug activity; nonhuman; adenocarcinoma; t lymphocyte; animal cell; mouse; animals; mice; animal experiment; animal model; colonic neoplasms; antineoplastic activity; transfection; mice, inbred balb c; gene transfer; genetic vectors; cancer inhibition; gene expression regulation, neoplastic; cellular immunity; chemokine; gamma interferon; probability; cd4-positive t-lymphocytes; cytotoxic t lymphocyte; gene therapy; neoplasms, experimental; tumor immunity; rats; adenovirus vector; disease models, animal; cell activation; statistics, nonparametric; adoptive immunotherapy; knockout mouse; cd86 antigen; complementary dna; adenoviridae; spleen cell; major histocompatibility antigen class 1; adenovirus; chemokines, cc; male; priority journal; article; macrophage derived chemokine
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