Is interleukin-1 a good or bad 'guy' in tumor immunobiology and immunotherapy?
ABSTRACT The interleukin-1 (IL-1) family consists of two major agonistic proteins, IL-1alpha and IL-1beta, which are pleiotropic and affect mainly inflammation, immunity, and hemopoiesis. The IL-1 receptor antagonist (IL-1Ra) is a physiological inhibitor of pre-formed IL-1. In their secreted form, IL-1alpha and IL-1beta bind to the same receptors and induce the same biological functions. However, the IL-1 molecules differ in their compartmentalization within the producing cell or the microenvironment. Thus, IL-1beta is solely active in its secreted form, whereas IL-1alpha is mainly active in cell-associated forms (intracellular precursor and membrane-bound IL-1) and only rarely as a secreted cytokine, mainly by macrophages/monocytes. IL-1 is abundant at tumor sites, being produced by cellular elements of the tumor microenvironment or by the malignant cells, and it affects not only various phases of the malignant process, such as carcinogenesis, tumor growth, and invasiveness, but also patterns of interactions between malignant cells and the host's immune system. Hence, the effects of the IL-1 molecules on the malignant process are complex and are often of an opposing nature. Comparative studies on the differential roles of malignant cell- or host-derived IL-1alpha and IL-1beta in different stages of the malignant process can subsequently open new avenues for manipulation of IL-1 expression and function in cancer immunotherapy.
[show abstract] [hide abstract]
ABSTRACT: The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction.Clinical and Developmental Immunology 01/2012; 2012:124187. · 1.84 Impact Factor
Article: Myeloid-Derived Suppressor Cells Interact with Tu-mors in Terms of Myelopoiesis, Tumorigenesis and Immunosuppression: Thick as Thieves[show abstract] [hide abstract]
ABSTRACT: Tumor progression is often associated with chronic inflammation in the tumor microenvi-ronment, which is mediated by numerous cytokines, chemokines and growth factors pro-duced by cancer and stroma cells. All these mediators support tumor development and immunosuppression in autocrine and/or paracrine ways. Neutralization of chronic inflam-matory conditions can lead to the restoration of anti-tumor immune responses. Among stroma cells infiltrating tumors, myeloid-derived suppressor cells (MDSCs) represent one of the most important players mediating immunosuppression. These cells may not only inhibit an anti-tumor immunity but also directly stimulate tumorigenesis as well as tumor growth and expansion. Therefore, understanding the mechanisms of generation, migration to the tumor site and activation of MDSC is necessary for the development of new strategies of tumor immunotherapy.Journal of Cancer. 01/2013; 4(1):3-11.
Article: MicroRNA profiling of Epstein-Barr virus-associated NK/T-cell lymphomas by deep sequencing.[show abstract] [hide abstract]
ABSTRACT: The Epstein-Barr virus (EBV) is an oncogenic human Herpes virus involved in the pathogenesis of nasal NK/T-cell lymphoma. EBV encodes microRNAs (miRNAs) and induces changes in the host cellular miRNA profile. MiRNAs are short non-coding RNAs of about 19-25 nt length that regulate gene expression by post-transcriptional mechanisms and are frequently deregulated in human malignancies including cancer. The microRNA profiles of EBV-positive NK/T-cell lymphoma, non-infected T-cell lymphoma and normal thymus were established by deep sequencing of small RNA libraries. The comparison of the EBV-positive NK/T-cell vs. EBV-negative T-cell lymphoma revealed 15 up- und 16 down-regulated miRNAs. In contrast, the majority of miRNAs was repressed in the lymphomas compared to normal tissue. We also identified 10 novel miRNAs from known precursors and two so far unknown miRNAs. The sequencing results were confirmed for selected miRNAs by quantitative Real-Time PCR (qRT-PCR). We show that the proinflammatory cytokine interleukin 1 alpha (IL1A) is a target for miR-142-3p and the oncogenic BCL6 for miR-205. MiR-142-3p is down-regulated in the EBV-positive vs. EBV-negative lymphomas. MiR-205 was undetectable in EBV-negative lymphoma and strongly down-regulated in EBV-positive NK/T-cell lymphoma as compared to thymus. The targets were confirmed by reporter assays and by down-regulation of the proteins by ectopic expression of the cognate miRNAs. Taken together, our findings demonstrate the relevance of deregulated miRNAs for the post-transcriptional gene regulation in nasal NK/T-cell lymphomas.PLoS ONE 01/2012; 7(8):e42193. · 4.09 Impact Factor