Tumor‐specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti‐tumor immunity

Abstract

Interleukin (IL-) 27 is a member of IL-12 cytokine family with Th1-promoting and anti-inflammatory effects. IL-27 has been shown to facilitate tumor-specific cytotoxic T lymphocyte (CTL) induction against various tumors. However, IL-27 suppresses cytokine production of lymphocytes and antigen-presenting function of dendritic cells (DCs). To examine the in vivo role of IL-27 in generation of anti-tumor immunity, we examined IL-27-mediated antitumor-effects using WSX-1 (IL-27 receptor a chain)-deficient (WSX-1 2/2 ) mice. In WSX-1 2/2 mice inoculated with B16 melanoma cells, tumor growth was higher than in wild-type (WT) mice. Accordingly, tumor-specific CTL generation was lower in WSX-1 2/2 mice than in WT mice. CTL induction in WSX-1 2/2 mice was not restored by transfer of WT DCs pulsed with TRP2 peptide, indicating that IL-27 is directly required for generation of tumor-specific CTLs. However, when transferred into tumorbearing mice, WSX-1 2/2 DCs pulsed with TRP2 peptide was more potent than WT DCs in tumor growth inhibition and generation of CTLs, indicating suppressive effects of IL-27 on DC function. Finally, the combination of WT CD8 1 T cells and KO DCs is more potent in generation of antigen-specific CTLs than any other combinations. Expression of perforin gene and percentages of tumor-specific CD8 1 T cells were also the highest in the combination of WT CD81 T cells and WSX-1 2/2 DCs. It was thus revealed that IL-27 promotes CTL generation while suppressing DC function during generation of tumor immunity. The combination of WT T cells and IL-27 signal-defective DCs may have therapeutic potential against tumors.

Loxoribine, a selective Toll-like receptor 7 agonist, induces maturation of human monocyte-derived dendritic cells and stimulates their Th-1- and Th-17-polarizing capability

“…Our study is the first one showing that signaling through TLR7 up-regulated IL-27 production by MoDCs which could be beneficial for stimulation of anti-tumor immunity. This hypothesis is in line with the knowledge that IL-27 acts in synergy with IL-12p70 to promote Th1 polarization in the early phase of immune response [38,39], to suppress Th2 differentiation [40] and to generate cytotoxic T-lymphocytes [41].…”

The Immunobiology of Interleukin-27

“…The efficacy of IL-27 in promoting the effector function of CD8 + T cells is illustrated by a number of in vivo studies that used different cancer cell lines engineered to express IL-27. In these experiments, IL-27 promoted tumor-specific cytotoxic T cell responses, tumor regression, and, in some cases, complete remission with memory responses to subsequent challenge (109)(110)(111)(112)(113)(114).…”

Autoimmune response induced by dendritic cells exerts anti-tumor effect in murine model of leukemia

“…Dendritic cells-based immunotherapy has been used in patients with melanoma, lymphoma, renal cell carcinoma, colon, breast, ovarian, and prostate cancer, with evidence of enhanced T cells immunity and, in some cases, with clinical benefits [25][26][27][28][29][30][31]. In some studies, when vaccination of dendritic cells loaded with tumor antigens shared with normal host cells results in severe autoimmune disease with the suppression of tumor [32].…”