Interleukin-23 and Interleukin-27 Exert Quite Different Antitumor and Vaccine Effects on Poorly Immunogenic Melanoma

Abstract

Recent studies revealed that two novel interleukin (IL)-12-related cytokines, IL-23 and IL-27, have potent antitumor activities. However, the antitumor effects were mainly evaluated in relatively highly immunogenic tumors and have not been fully evaluated against nonimmunogenic or poorly immunogenic tumors. In this study, we investigated the antitumor efficacies of IL-23 and IL-27 on poorly immunogenic B16F10 melanoma and found that the antitumor responses mediated by IL-23 and IL-27 were clearly different. In syngeneic mice, mouse single-chain (sc) IL-23-transfected B16F10 (B16/IL-23) tumors exhibited almost the same growth curve as B16F10 parental tumor about until day 20 after tumor injection and then showed growth inhibition or even regression. In contrast, scIL-27-transfected B16F10 (B16/ IL-27) tumors exhibited significant retardation of tumor growth from the early stage. In vivo depletion assay revealed that the antitumor effect of B16/IL-23 was mainly mediated by CD8 + T cells and IFN-; whereas that of B16/IL-27 mainly involved natural killer cells and was independent of IFN-;. We also found that antitumor effects of B16/IL-23 and B16/IL-27 were synergistically enhanced by treatment with IL-18 and IL-12, respectively. Furthermore, B16/IL-23-vaccinated mice developed protective immunity against parental B16F10 tumors but B16/IL-27-vaccinated mice did not. When combined with prior in vivo depletion of CD25 + T cells, 80% of B16/ IL-23-vaccinated mice completely rejected subsequent tumor challenge. Finally, we showed that the systemic administration of neither IL-23 nor IL-27 induced such intense toxicity as IL-12. Our data support that IL-23 and IL-27 might play a role in future cytokine-based immunotherapy against poorly immunogenic tumors. (Cancer Res 2006; 66(12): 6395-404)

IL-27 Directly Restrains Lung Tumorigenicity by Suppressing Cyclooxygenase-2-Mediated Activities

“…In contrast to IL-12, IL-27 acts on naive CD4 ϩ T cells and regulates only the initiation phase of Th1 responses. Thus, IL-27-treated mice are not observed with any apparent adverse effects (8,45).…”

Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model

“…An additional argument in favor of our proposal is the low toxicity shown by IL-27 in animal models, likely in relation to the low induction of IFN-g in vivo. 9 Finally, simultaneous activation of in vivo antitumor effector mechanisms mediated by cytotoxic T lymphocytes , natural killer and CD8 þ T cells may be induced by IL-27. 1 …”

New insights into IL-12-mediated tumor suppression

“…149 The mechanisms that drive IL-27 antitumor effects include inhibition of angiogenesis [150][151][152] and tumor cell proliferation, 153,154 and the activation of CD8 þ T and NK cells. 155,156 As IL-27 acts only on naive T cells, the concentrations of IL-27-induced pro-inflammatory cytokines are presumably not high enough to induce the appearance of adverse side effects. 157 IL-35 was initially described as a Treg-specific cytokine with potent immunosuppressive properties.…”