Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 3; pp. 1063 - 1070
• Main Authors: QIAO LI, CARR, Abbey L, DONALD, Elizabeth J, SKITZKI, Joseph J, OKUYAMA, Ryugi, STOOLMAN, Lloyd M, CHANG, Alfred E
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2005
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antineoplastic agents; Biological and medical sciences; CD28 Antigens - immunology; CD3 Complex - immunology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cytokines - immunology; Cytokines - secretion; Drug Synergism; Female; Fibrosarcoma - immunology; Fibrosarcoma - therapy; Interleukin-12 - immunology; Interleukin-12 - pharmacology; Interleukin-18 - immunology; Interleukin-18 - pharmacology; Lymph Nodes - drug effects; Lymph Nodes - immunology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Sequence Data; NF-kappa B - antagonists & inhibitors; NF-kappa B - immunology; Pharmacology. Drug treatments; Signal Transduction - immunology; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Th1 Cells - drug effects; Th1 Cells - immunology; Interleukin 12; Immune response; Synergism; Tumor cell; Cytokine
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.1063.65.3

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.