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IL-12, IL-23, IL-27, and IL-35 are the four heterodimeric cytokines with variable but consistent structural homology that constitute the IL-12/IL-23 cytokine family. These cytokines bind heterodimeric receptors, which activate different signal transducer and activation of transcription molecules. A distinctive feature of the IL-12/IL-23 family is that both cytokines and their receptors share different subunits, pointing to the great plasticity of the system. IL-12, IL-23, and IL-27 are all produced by antigen-presenting cells (monocytes, macrophages, dendritic cells) upon Toll-like receptor triggering. IL-35 is produced by different subsets of T regulatory (Treg) cells and B regulatory (Breg) cells. All IL-12/IL-23 family cytokines control in different ways the differentiation of T helper (Th) cells along the Th1, Th17, Th2, and Treg lineages. IL-23 and IL-12 are implicated in the pathogenesis of various autoimmune disorders and their targeting with monoclonal antibodies has proven efficacious in the clinical setting. All cytokines of the family modulate tumor growth by acting on the tumor microenvironment and/or directly on cancer cells. In essence, the discovery of the IL-12/IL-23 family cytokines had greatly advanced the fields of immune regulation, autoimmunity, and tumor immunology.

Neuroblastoma (NB) is a pediatric extracranial tumor characterized by downregulation of human leukocyte antigen class I and defects of the antigen processing machinery, two features that make it an appropriate target for natural killer (NK)-mediated lysis. NKG2D is an activating immunoreceptor expressed by cytotoxic T lymphocytes and NK cells. The ligands for NKG2D are the major histocompatibility complex class I-related chain (MIC)A and MICB glycoproteins, and the UL-16-binding proteins (ULBPs). Here, the expression of NKG2D ligands was investigated in human primary NB tumors and cell lines because scanty information is available on this issue. MICA, MICB, and ULBP transcripts were found in most tumors and cell lines. MICA protein was detected in some NB cell lines but not in primary tumors. A soluble form of MICA (sMICA) was identified in most patient sera and in some cell line supernatants. sMICA downregulated surface NKG2D in normal peripheral blood CD8+ cells and decreased NK-mediated killing of MICA+ NB cells. MICB was detected exclusively in the cytosol of primary tumors and cell lines. Approximately 50% of primary tumors expressed ULBP-2, but not ULBP-1 or -3. ULBP-3 was expressed in 5 of 9 cell lines, ULBP-2 in 2 of 9, whereas ULBP-1 was never detected. These studies delineate novel potential pathways of tumor escape and immunodeficiency in NB.

Glutathione (GSH) depletion is widely used to sensitize cells to anticancer treatment inducing the progression of programmed cell death and overcoming chemoresistance. It has been reported that neuroblastoma cells with MYCN amplification are unable to start TRAIL-dependent death and MYCN, in concert with cytotoxic drugs, efficiently induces the mitochondrial pathway of apoptosis through oxidative mechanisms. In this study, we show that GSH loss induced by L-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH biosynthesis, leads to overproduction of reactive oxygen species (ROS) and triggers apoptosis of MYCN-amplified neuroblastoma cells. BSO susceptibility of SK-N-BE-2C, a representative example of MYCN-amplified cells, has been attributed to stimulation of total SOD activity in the absence of changes in the level and the activity of catalase. Therefore, the unbalanced intracellular redox milieu has been demonstrated to be critical for the progression of neuroblastoma cell death that was efficiently prevented by antioxidants and rottlerin. These results describe a novel pathway of apoptosis dependent on ROS formation and PKC-delta activation and independent of p53, bcl-2, and bax levels; the selective redox modulation of PKC-delta might be suggested as a potential strategy for sensitizing MYCN-amplified cells to therapeutic approaches.