title: Synergistic effect of intratumoral IL-12 and TNF-alpha microspheres: systemic anti-tumor immunity is mediated by both CD8+ CTL and NK cells.
abstract: Neoadjuvant immunotherapy with the combination of intratumoral IL-12 and TNF-alpha encapsulated in poly-lactic acid microspheres (PLAM) generate a greater systemic immune response than either cytokine alone. We sought to examine the effector cells responsible for this synergy using the poorly immunogenic B16 melanoma and MCA205 sarcoma cell lines. Splenocytes from MCA205 bearing mice treated with IL-12 and TNF-alpha PLAM contained significantly more tumor-specific IFN-gamma secreting cells than IL-12 alone. Adoptive transfer of lymphocytes from mice treated by the combination mediated significant tumor regression in mice bearing established pulmonary metastases. In mice bearing bilateral tumors, treatment of the primary with IL-12 and TNF-alpha PLAM, resulted in suppression of contralateral tumor growth. Both the local and distant effects were absent in mice depleted of CD8+ T-cells. In B16 bearing mice with established pulmonary disease, only the combination of intratumoral IL-12 and TNF-alpha resulted in a significant reduction of lung nodules. Both the local and distant effects were eradicated in mice depleted of either CD8+ T-cells or NK cells. The local and sustained release of IL-12 and TNF-alpha using PLAM synergistically activate both a cytotoxic T-cell and NK cell response, although their impact varies with MHC class I expression.
authors.affiliation: Division of Surgical Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. msabel@umich.edu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sabel
authors.forename: Alisha
authors.initials: A
authors.lastname: Arora
authors.forename: Gang
authors.initials: G
authors.lastname: Su
authors.forename: Edith
authors.initials: E
authors.lastname: Mathiowitz
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Reineke
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods; D018664:Interleukin-12 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009368:Neoplasm Transplantation; D012509:Sarcoma / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12