ABSTRACT
Interferon-gamma-inducible protein 10 is a potent chemoattractant for natural killer cells and activated T lymphocytes. It also displays angiostatic properties and some antitumor activity. Tumor necrosis factor-alpha (TNF-alpha) is a powerful immunomodulating cytokine with demonstrated tumoricidal activity in various tumor models and the ability to induce strong immune responses. This prompted us to evaluate the antitumor effects of recombinant parvoviruses designed to deliver IP-10 or TNF-alpha into a glioblastoma. When Gl261 murine glioma cells were infected in vitro with an IP-10- or TNF-alpha-transducing parvoviral vector and were subcutaneously implanted in mice, tumor growth was significantly delayed. Complete tumor regression was observed when the glioma cells were coinfected with both the vectors, demonstrating synergistic antitumor activity. In an established in vivo glioma model, however, repeated simultaneous peritumoral injection of the IP-10- and TNF-alpha-delivering parvoviruses failed to improve the therapeutic effect as compared with the use of a single cytokine-delivering vector. In this tumor model, cytokine-mediated immunostimulation, rather than inhibition of vascularization, is likely responsible for the therapeutic efficacy.
Subject(s)
Chemokine CXCL10/metabolism , Chemokine CXCL10/therapeutic use , Glioblastoma/drug therapy , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/therapeutic use , Animals , Chemokine CXCL10/administration & dosage , Chemokine CXCL10/immunology , Dendritic Cells/cytology , Dendritic Cells/virology , Drug Synergism , Female , Genetic Vectors , Glioblastoma/blood supply , Glioblastoma/immunology , Glioblastoma/metabolism , Glioblastoma/virology , H-1 parvovirus/physiology , Humans , Immunocompetence , Mice , Mice, Inbred C57BL , Minute Virus of Mice/physiology , Necrosis/metabolism , Tumor Cells, Cultured/cytology , Tumor Cells, Cultured/drug effects , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Cutaneous T-cell lymphomas (CTCL) are mainly comprised of two variants: mycosis fungoides (MF) with CD4(+) tumor cells confined to the skin and the leukemic Sézary syndrome with tumor cell spread to the blood. In this study, we investigated cutaneous expression of the regulatory T-cell (T(reg)) marker FOXP3 in 30 CTCL patients. Immunohistochemical analysis revealed significantly lower numbers of CD4(+)FOXP3(+) cells within the dermal lymphomononuclear infiltrate of Sézary patients (16% FOXP3(+) cells of CD4(+) cells) in contrast to MF (43% FOXP3(+) cells (P<0.05)) and rare types of CTCL (45% FOXP3(+) cells). Furthermore, CD4(+)FOXP3(+) T cells were also markedly reduced in the CD4(+) population within the peripheral blood of Sézary patients compared to controls as determined by fluorescence-activated cell sorter, quantitative PCR and functional analyses. The data support the conclusion that the neoplastic cells in CTCL do not express the T(reg) marker FOXP3. Our data also identify Sézary syndrome as, to our knowledge, the first reported neoplastic disease with a clear reduction in T(reg) numbers within the CD4(+) population. This lack of T(reg) might account for the more aggressive nature of Sézary syndrome compared with other CTCL.
