Mitochondria are indispensable for energy metabolism, apoptosis regulation, and cell signaling. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and participate actively in metabolic reprogramming. Mitochondria in cancer cells are characterized by reactive oxygen species (ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression, and participating in signaling pathways. Mitochondrial and nuclear DNA mutations caused by oxidative damage that impair the oxidative phosphorylation process will result in further mitochondrial ROS production, completing the "vicious cycle" between mitochondria, ROS, genomic instability, and cancer development. The multiple essential roles of mitochondria have been utilized for designing novel mitochondria-targeted anticancer agents. Selective drug delivery to mitochondria helps to increase specificity and reduce toxicity of these agents. In order to reduce mitochondrial ROS production, mitochondria-targeted antioxidants can specifically accumulate in mitochondria by affiliating to a lipophilic penetrating cation and prevent mitochondria from oxidative damage. In consistence with the oncogenic role of ROS, mitochondria-targeted antioxidants are found to be effective in cancer prevention and anticancer therapy. A better understanding of the role played by mitochondria in cancer development will help to reveal more therapeutic targets, and will help to increase the activity and selectivity of mitochondria-targeted anticancer drugs. In this review we summarized the impact of mitochondria on cancer and gave summary about the possibilities to target mitochondria for anticancer therapies. J. Cell. Physiol. 231: 2570-2581, 2016. © 2016 Wiley Periodicals, Inc.

Reactive oxygen species (ROS) are a group of highly reactive chemicals containing oxygen produced either exogenously or endogenously. ROS are related to a wide variety of human disorders, such as chronic inflammation, age-related diseases and cancers. Besides, ROS are also essential for various biological functions, including cell survival, cell growth, proliferation and differentiation, and immune response. At present there are a number of excellent publications including some reviews about functions of these molecules either in normal cell biology or in pathophysiology. In this work, we reviewed available information and recent advances about ROS in the main immune cell types and gave summary about functions of these highly reactive molecules both in innate immunity as conservative defense mechanisms and in essential immune cells involved in adaptive immunity, and particularly in immune suppression.

The aim of this study was to investigate whether depletion of CD4 1 CD251 regulatory T cells (Treg) from melanoma patients affects immune responses against tumors. By application of recombinant IL-2-diphteria toxin fusion protein, also known as ONTAK, we were able to significantly reduce the frequency of Treg in peripheral blood, whereas other cell populations remained unaffected. The reduction of Treg started immediately after the first bolus of ONTAK with a dose of 5 lg ONTAK per kg bodyweight and lasted for 13 days with subsequent recovery thereafter. Successive ONTAK treatments further reduced the number of circulating Treg. Using the contact sensitizer DCP we show that all patients developed vast eczema after Treg depletion, whereas no or only mild eczematous reactions were detectable before ONTAK treatment. Corresponding induction of DCP-specific CD4 1 and CD8 1 T cells were detectable. Moreover, after immunization of ONTAK treated patients with tumor antigen peptides, MelanA/ MART-1 and gp100, significant induction of peptide specific CD8 1 T cells could be observed in 90% of the patients treated. These cells displayed effector functions, as they were able to lyse peptide-pulsed target cells and secreted IFNc upon restimulation. In aggregate, our data indicate that ONTAK depletes Treg in vivo significantly, resulting in enhanced immune functions and substantial development of antigen-specific CD8 1 T cells in vaccinated individuals. ' 2007 Wiley-Liss, Inc.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate. Immunosuppressive cell populations, e.g. regulatory T cells (Treg), appear to be important in PDAC, contributing to patient's poor prognosis. Therefore, we investigated the PDAC microenvironment with a focus on conventional and regulatory T cells in view of their potential therapeutic importance. We found that tumors from the murine Panc02 orthotopic model of PDAC were infiltrated with high numbers of Treg. Remarkably, these cells exhibited the effector/memory phenotype, suggesting their enhanced suppressive activity and higher proliferation capacity. Although we observed a steady increase in transforming growth factor-b (TGF-b) levels in the tumors, treatment with a specific inhibitor of TGF-b receptor I kinase failed to abrogate Treg accumulation. A CCR4 antagonist did not affect Treg percentage in the tumor either. However, intense Treg cell division in the tumor microenvironment was demonstrated, suggesting local proliferation as a major mechanism of Treg accumulation in PDAC. Notably, this accumulation was reduced by low-dose gemcitabine administration, resulting in a modestly increased survival of PDAC mice. Our results provide an insight into mechanisms of immunosuppression in PDAC, suggesting an important role for proliferative expansion of effector/memory Treg. Low-dose gemcitabine therapy selectively depletes Treg, providing a basis for new modalities of PDAC therapy.Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms having extremely poor prognosis with a 5-year survival rate of <1% and a median survival of 6 months. Even after surgical intervention, the 5-year survival rate is at best 15% without adjuvant therapy or 25% with adjuvant chemotherapy. 1 In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. The molecular mechanisms that determine treatment resistance are poorly understood.

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Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. PDAC cells activate tumor-specific immune responses but simultaneously trigger a strong immunosuppression. We showed that PDAC cells produce high amount of chronic inflammatory mediators and PDAC tumors build an immunosuppressive cytokine milieu, which correlates with tumor progression. We observed a low frequency of dendritic cells (DC) and a pronounced accumulation of macrophages and myeloid-derived suppressor cells (MDSC) in murine PDAC tumors. A strong accumulation of MDSC has also been demonstrated in the peripheral blood of resected PDAC patients. While DC and macrophages seem not to play a significant role in this PDAC model in the context of immunosuppression, MDSC are highly suppressive, and their accumulation is associated with an increase in intratumoral VEGF concentration during the PDAC progression. Application of the phosphodiesterase-5 inhibitor sildenafil led to a prolonged survival of PDACbearing female mice, which was due to the decrease in MDSC frequencies and in the systemic VEGF level. This led to a restoration of anticancer immune responses, manifested in the recovery of T lymphocyte functions and in an increase in the frequency of conventional CD4 C T cells in tumors and IFNg level in serum of PDAC-bearing mice. Thus, MDSC are strongly involved in the PDAC-associated immunosuppression and that their depletion could create new approaches for therapy of PDAC.

IL-27, an IL-12 family member, was initially described as a proinflammatory cytokine. Nevertheless, it also poses anti-inflammatory activity, being involved in suppressing development of TH-17 cells as well as in the induction of inhibitory Tr1 cells. Recent data obtained in mice suggest that it can down-modulate the function of APCs. However, until now, nothing was known about the influence of IL-27 on human DCs. We investigated the effect of IL-27 on in vitro human MoDCs and on ex vivo blood DCs. Our results show that treatment of mDCs with IL-27 led to specific up-regulation of surface expression of several molecules, including B7-H1, in the absence of general DC maturation. Moreover, we demonstrated that IL-27-treated DCs exhibit a reduced capacity to stimulate proliferation and cytokine production of allogeneic T cells as compared with control DCs. Decisively, we identified B7-H1 as a crucial molecule, responsible for suppressive effects of "IL-27 DC" on T cells. Our data demonstrate for the first time that in addition to the dual role of IL-27 in the modulation of T cell activation and differentiation, human IL-27 modulates an immune response through DCs, i.e., by inducing immunosuppressive B7-H1 molecules and reducing the stimulatory potential of DCs.

Interferon-α (IFNα) has one of the longest histories of use amongst cytokines in clinical oncology and has been applied for the treatment of many types of cancers. Due to its immune-activating properties, IFNα is also an attractive candidate for combinatory anti-cancer therapies. Despite its extensive use in animal tumor models as well as in several clinical trials, the different mechanisms underlying patient responses and affecting desirable clinical benefits are still under investigation. Here we show that in addition to its immune-activating properties, IFNα induces the expression of a key negative regulator, immunosuppressive PD-L1 molecule, in the majority of the specific immune cell populations, particularly in the dendritic cells (DC). DC can modulate immune responses by a variety of mechanisms, including expression of T-cell regulatory molecules and cytokines. Our results showed that treatment of DC with IFNα-2b led to pronounced up-regulation of surface expression of PD-L1 molecules, increased IL-6 and decreased IL-12 production. Moreover, we present evidence that IFNα-treated DC exhibited a reduced capacity to stimulate interferon-γ production in T cells compared to control DC. This T-cell response after treatment of DC with IFNα was recovered by a pre-treatment with an anti-PD-L1 blocking antibody. Further analyses revealed that IFNα regulated PD-L1 expression through the STAT3 and p38 signaling pathways, since blocking of STAT3 and p38 activation with specific inhibitors prevented PD-L1 up-regulation. Our findings underline the important roles of p38 and STAT3 in the regulation of PD-L1 expression and prove that IFNα induces STAT3/p38-mediated expression of PD-L1 and thereby a reduced stimulatory ability of DC. The augmentation of PD-L1 expression in immune cells through IFNα treatment should be considered by use of IFNα in an anti-cancer therapy.