The Roles of Interleukin-27 in Tumor Immunity.

摘要

Interleukin-27 (IL-27) is a member of the IL-12 family of cytokines. IL-27 is a heterodimer consisting of an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3) and a p35-related subunit, p28. IL-27 is mainly produced by activated antigen presenting cells. It functions through engaging IL-27 receptor, which is expressed on a variety of immune cell types, including CD4+ and CD8+ T cells. Overexpression of IL-27 by tumor cells exerts potent anti-tumor activity through diverse mechanisms, in which CD8+ T cells were considered to be the main effector cells. However, the exact mechanisms by which IL-27 enhances anti-tumor CD8+ T cell response and leads to tumor rejection remain unclear.;The impacts of IL-27 on the differentiation and activation of CD8 + T cells were studied by stimulating naive tumor antigen-specific CD8+ T cells (P1CTL) with cognate P1A peptide in the presence and absence of IL-27. First, T cell proliferation and apoptosis were examined by thymidine incorporation and Annexin V/7-AAD staining, respectively. Second, expressions of activation and differentiation markers of T cells were analyzed by Real time PCR and Western Blotting. Third, cytokine production was evaluated by ELISA and flow cytometry. To investigate the in vivo roles of IL-27 in tumor immunity, mouse models involving tumor cells (J558 plasmacytoma and B16 melanoma) expressing IL-27 and IL-27-deficient (EBI3-/-) mice were used. To delineate the mechanisms by which IL-27 enhances antitumor CTL responses, tumor antigen specific CD8+ T cells were adoptively transferred into various genetically engineered mice with established tumors, and their in vivo proliferation and apoptosis were studied by CSFE staining and flow cytometry analysis. To examine the role of IL-27 in response and function of T regulatory cells, Anti-CD25 antibody was used to deplete Treg cells; IL-27 deficient or WT CD4+CD25 + Treg cells were adoptively transferred together with effector T cells into tumor-bearing mice; tumor establishment and metastases were evaluated by monitoring s.c. tumor growth and weighing lungs, respectively.;Overall, we have uncovered four novel findings that can explain why IL-27 boosts antitumor CD8+ T cell responses:;1) IL-27 enhances the survival of activated tumor antigen specific CD8 + T cells both in vitro and in vivo..;2) IL-27 induces a unique memory precursor cell (MPC) phenotype in activated tumor antigen specific CD8+ T cells, which is characterized by up-regulation of SOCS3, Bcl-6, Sca-1 and IL-10.;3) IL-27 robustly induces IL-10 production by tumor antigen specific CD8+ T cells, which contributes to IL-27-mediated tumor rejection in vivo..;4) IL-27 inhibits the expansion and immunesuppressive ability of CD4 +FoxP3+ T regulatory cells, resulting in more potent anti-tumor CTL responses.;Our findings suggest that:;1) IL-27 has the potential to be used as an adjuvant to boost the efficacy of antitumor vaccines;;2) IL-27 can be used to culture tumor antigen-specific CTLs for adoptive transfer therapy of cancer patients.