title: Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern.
abstract: We have previously described the antitumor reactivity of tumor-draining lymph node (TDLN) cells after secondary activation with antibodies. In this report, we examined the effects of interleukin (IL)-12 and IL-18 on modulating the immune function of antibody-activated murine TDLN cells. TDLN cells were activated with anti-CD3/anti-CD28 monoclonal antibody followed by stimulation with IL-12 and/or IL-18. IL-18 in combination with IL-12 showed a synergistic effect in augmenting IFNgamma and granulocyte macrophage colony-stimulating factor secretion, whereas IL-18 alone had minimal effect. Concurrently, IL-18 prevented IL-12-stimulated TDLN cells from producing IL-10. The IL-12/IL-18-cultured TDLN cells therefore manifested cytokine responses skewed towards a Th1/Tc1 pattern. IL-12 and IL-18 stimulated CD4(+) TDLN cells and enhanced IFNgamma production by CD4(+) cells to a greater extent than by CD8(+) cells. Use of NF-kappaB p50(-/-) TDLN cells suggested the involvement of NF-kappaB in the IL-12/IL-18 polarization effect. Furthermore, a specific NF-kappaB inhibitor significantly suppressed IL-12/IL-18-induced IFNgamma secretion, thus confirming the requirement for NF-kappaB activation in IL-12/IL-18 signaling. In adoptive immunotherapy, IL-12- and IL-18-cultured TDLN cells infiltrated pulmonary tumor nodules and eradicated established tumor metastases more efficiently than T cells generated with IL-12 or IL-18 alone. Antibody depletion revealed that both CD4(+) and CD8(+) cells were involved in the tumor rejection induced by IL-12/IL-18-cultured TDLN cells. These studies indicate that IL-12 and IL-18 can be used to generate potent CD4(+) and CD8(+) antitumor effector cells by synergistically polarizing antibody-activated TDLN cells towards a Th1 and Tc1 phenotype.
authors.affiliation: Departments of Surgery and Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109-0932, USA. qiaoli@umich.edu
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.forename: Abbey L
authors.initials: AL
authors.lastname: Carr
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Donald
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Skitzki
authors.forename: Ryugi
authors.initials: R
authors.lastname: Okuyama
authors.forename: Lloyd M
authors.initials: LM
authors.lastname: Stoolman
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000628:therapy; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D020382:Interleukin-18 / Q000276:immunology / Q000494:pharmacology*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D020382:Interleukin-18; D016328:NF-kappa B; D018664:Interleukin-12