Tumor-specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti-tumor immunity (original) (raw)
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The role of IL-27 in the induction of anti-tumor cytotoxic T lymphocyte response
American journal of translational research, 2013
Cytotoxic T lymphocyte (CTL) response is a critical component of the immune response to tumors, therefore optimal induction of CTL responses to tumor antigens is highly desired for developing efficient cancer immunotherapy. IL-27 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3), and a p35-related subunit, p28. IL-27 functions through IL-27R and has been shown to have potent anti-tumor activity via activation of a variety of immune components, including anti-tumor CD8(+) T cell responses. However, the exact mechanisms of how IL-27 enhances anti-tumor CD8(+) T cell responses are not fully understood. In this paper we mainly discuss the evidences that suggest novel mechanisms by which IL-27 enhances anti-tumor CTL responses, including IL-27 inhibition of activation-induced cell death; the phenotypes of IL-27-stimulated CTLs; IL-27-induced CTL IL-10/IL-21 production and IL-27-mediated suppression of regulat...
BioMed Research International
Cytotoxic T lymphocytes (CTLs) play a critical role in the control of various cancers and infections, and therefore the molecular mechanisms of CTL generation are a critical issue in designing antitumor immunotherapy and vaccines which augment the development of functional and long-lasting memory CTLs. Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, acts on naive CD4 + T cells and plays pivotal roles as a proinflammatory cytokine to promote the early initiation of type-1 helper differentiation and also as an antiinflammatory cytokine to limit the T cell hyperactivity and production of pro-inflammatory cytokines. Recent studies revealed that IL-27 plays an important role in CD8 + T cells as well. Therefore, this article reviews current understanding of the role of IL-27 in CD8 + T cell functions and generation of CTLs.
Interleukin-27 Signaling Promotes Immunity against Endogenously Arising Murine Tumors
PLoS ONE, 2013
Interleukin-27 (IL-27) is a pleiotropic cytokine but its immunosuppressive effects predominate during many in vivo immunological challenges. Despite this, evidence from tumor cell line transfer models suggested that IL-27 could promote immune responses in the tumor context. However, the role of IL-27 in immunity against tumors that develop in situ and in tumor immunosurveillance remain undefined. In this study, we demonstrate that tumor development and growth are accelerated in IL-27 receptor a (Il27ra)-deficient mice. Enhanced tumor growth in both carcinogen-induced fibrosarcoma and oncogene-driven mammary carcinoma was associated with decreased interferon-c production by CD4 and CD8 T cells and increased numbers of regulatory T-cells (T reg). This is the first study to show that IL-27 promotes protective immune responses against endogenous tumors, which is critical as the basis for future development of an IL-27 based therapeutic agent.
European Journal of Immunology, 2013
IL-27 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p40-related protein subunit, EBV-induced gene 3, and a p35-related subunit, p28. IL-27 functions through IL-27R and has been shown to have potent antitumor activity via activation of a variety of cellular components, including antitumor CD8 + T-cell responses. However, the exact mechanisms of how IL-27 enhances antitumor CD8 + T-cell responses remain unclear. Here we show that IL-27 significantly enhances the survival of activated tumor antigen-specific CD8 + T cells in vitro and in vivo, and programs tumor antigen-specific CD8 + T cells into memory precursor-like effector cells, characterized by upregulation of Bcl-6, SOCS3, Sca-1, and IL-10. While STAT3 activation and the CTL survival-enhancing effects can be independent of CTL IL-10 production, we show here that IL-27-induced CTL IL-10 production contributes to memory precursor cell phenotype induction, CTL memory, and tumor rejection. Thus, IL-27 enhances antitumor CTL responses via programming tumor antigen-specific CD8 + T cells into a unique memory precursor type of effector cells characterized by a greater survival advantage. Our results have important implications for designing immunotherapy against human cancer.
Journal of Immunotherapy, 2010
The immune response to tumor can be enhanced by targeting costimulatory molecules on T cells. As the CD70-CD27 costimulatory axis plays an important role in the activation, survival and differentiation of lymphocytes, we have examined the efficacy of agonistic anti-CD27 antibodies as monotherapies for established melanoma in a murine model. We demonstrate that this approach leads to a substantial reduction in the outgrowth of both experimental lung metastases and sub-cutaneous tumors. Anti-CD27 treatment supports the maintenance of tumor-specific CD8 + T cells within the tumor, reduces the frequency of FoxP3-expressing CD4 + T cells within tumors, and potentiates the ability of NK1.1 + and CD8 + tumor infiltrating cells to secrete IFNγ upon coculture with tumor cells. The enhanced effector function correlated with lower levels of PD-1 expression on CD8 + T cells from anti-CD27 treated mice. Despite the modulating effect of anti-CD27 on multiple cell types, only CD8 + T cells were absolutely required for tumor control. CD4 + T cells were dispensable, while NK1.1 + cells were needed during early stages of tumor growth but not for the effectiveness of anti-CD27. Thus, CD27-mediated costimulation provides a potent boost to multiple aspects of the endogenous responses to tumor, and may be exploited to enhance tumor immunity.
European Journal of Immunology, 2012
Intrinsic immunosuppression is a major obstacle for a successful cancer therapy. Mechanisms how immunosuppression is induced and regulated in humans are ill-defined. A micro-environmental component that might prevent anti-tumor immunity is the presence of dying tumor cells, which is abundant following conventional cancer ablation methods such as chemo-or radiotherapy. Shedding of apoptotic debris and/or secretion of factors to the tumor bed or draining lymph nodes thus might have a profound impact on professional phagocytes such as DC and subsequent priming of lymphocytes. In this study, we exposed human DC to supernatants of living, apoptotic or necrotic human breast cancer cells and co-cultured them with autologous T cells. Priming with apoptotic debris prevented DC from establishing cytotoxicity towards living human tumor cells by inducing a regulatory T cell population, defined by co-expression of CD39 and CD69. Immunosuppression via Treg was transferable and required the release of sphingosine-1phosphate (S1P) from apoptotic cells, acting via S1P receptor 4 on DC to induce IL-27 secretion. We propose that CD69-expression on CD39 + Treg enables them to interact with CD73-expressing CD8 + T cells to generate adenosine, thereby suppressing cytotoxicity. These findings aid the understanding how dying tumor cells limit anti-tumor immunity.