title: Combination cytokine therapy inhibits tumor growth by generation of tumor-specific T-cell responses in a murine melanoma model.
abstract: Various cytokines, including interferon alpha (IFNalpha), tumor necrosis factor alpha (TNFalpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been used as adjuvant therapy for advanced-stage melanoma with some success but with marked toxicity, which appears to be related to higher doses. We investigated the efficacy of IFNalpha, GM-CSF, and TNFalpha in various combinations to induce antitumor and immune responses in a B16F10 murine melanoma model. These studies showed that GM-CSF, IFNalpha, and TNFalpha, when injected together intratumorally, mediated significant inhibition of tumor growth. Tumor regression correlated with local tumor necrosis and significant infiltration of T cells. In addition, this injected intralesional cytokine cocktail also induced lymphadenopathy, with an increase in both CD4(+) and CD8(+) T cells in the draining lymph nodes. Furthermore, tumor-specific CD8(+) T cells were identified from draining lymph nodes. These investigations identify the combined effects of IFNalpha, GM-CSF, and TNFalpha in induction of the adaptive immune response and generation of antigen-specific T-cell reactivity. These results support potential clinical trials of the low-dose cytokine combination as adjuvant therapy for melanoma.
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN 55905, USA. kalaaji.amer@mayo.edu
authors.forename: Amer N
authors.initials: AN
authors.lastname: Kalaaji
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pittelkow
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D016898:Interferon-alpha / Q000276:immunology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor