Svetlana Karakhanova's research while affiliated with Universität Heidelberg and other places

Publications (57)

Article
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Immune checkpoint molecule B7-H1 plays a decisive immune regulatory role in different pathologies including cancer, and manipulation of B7-H1 expression became an attractive approach in cancer immunotherapy. Pancreatic cancer (PDAC) is characterized by pronounced immunosuppressive environment and B7-H1 expression correlates with PDAC prognosis. How...
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Introduction: The broccoli isothiocyanate sulforaphane was shown to inhibit inflammation and tumor progression, also in pancreatic cancer, while its effect on tumor immunity is poorly understood. We investigated the immunoregulatory effect of sulforaphane on human dendritic cells alone and in presence of pancreatic tumor antigens, as well as under...
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Synthesis of extracellular adenosine by the ectonucleotidases CD39 and CD73 represents an important pathway of immune suppression in the tumor microenvironment. Using two mouse models (RET transgenic melanoma and Panc02 orthotopic pancreatic adenocarcinoma), we identified an elevated frequency of ectonucleotidase-expressing T cells in tumors and sp...
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Food-derived plant microRNAs are suggested to control human genes by "cross-kingdom" regulation. We examined microRNAs in sprouts from Brassica rapa sylvestris, known as broccoletti, which are widely used as sulforaphane supplements, and assessed their influence on pancreatic cancer. RNA was isolated from 4-day-old sprouts, followed by deep sequenc...
Article
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The therapy resistance of pancreatic cancer is associated with the loss of gap junction intercellular communication and connexin 43 expression. The broccoli isothiocyanate sulforaphane restored these features and therapy sensitivity. We investigated whether microRNA signaling is involved. Established cell lines and a patient tissue array (n=96) wer...
Article
NF-κB contributes to the aggressiveness of pancreatic ductal adenocarcinoma (PDA), which is counteracted by the bioactive agent sulforaphane. We investigated sulforaphane-induced microRNA signaling and its influence on progression features. Using established cell lines, microRNA and gene arrays, we predicted miR-365a as the top candidate for the su...
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Background/aims: The extracellular ecto-5'-nucleotidase (CD73) is involved in the production of immunosuppressive adenosin (Ado), which can influence different immune cells through the specific adenosine receptors. The main aim of this work was to characterize immune cell populations as well as serum cytokine level in healthy CD73-deficient mice c...
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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 severa...
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Activation of receptor tyrosine kinases is recognized as a hallmark of cancer. Vascular endothelial growth factor (VEGF) and its receptor VEGFR are the prominent players in the induction of tumor neoangiogenesis. Strategies to inhibit VEGF and VEGFR are under intensive investigation in preclinical and clinical settings. Regorafenib is a multikinase...
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Reactive oxygen species (ROS) are a group of highly reactive chemicals under tight control of intracellular antioxidants. The balance in oxidation-antioxidation is essential for maintaining normal cell functions, and any imbalance could lead to a wide range of diseases including cancer. The intracellular level of ROS is generally elevated in cancer...
Article
Our understanding in the last few years about reactive oxygen species (ROS) has changed from being harmful substances to crucial intra- and extracellular messengers as well as important regulators controlling a wide spectrum of signaling pathways, including those in cancer immunology. Therefore, these multiple essential roles of ROS and especially...
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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 prom...
Article
Orthotopic liver transplantation (LTP) is nowadays a standard procedure, and provides the chance of survival of patients with end-stage non-treatable chronic liver disease or acute liver failure. Despite long-term survival with a good quality of life in the majority of patients, about 20% develop early allograft dysfunction (EAD), which leads to de...
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In general conventional chemotherapy is associated with significant toxicity leading to immunosuppression manifesting mainly in the lymphocyte depletion. This immunosuppression promotes tumor growth and elicits the tumor cell dissemination. However, chemotherapy can be immune stimulative especially in combination with an immunotherapy. In this work...
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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Therefore, new therapeutic options are urgently needed to improve the survival of PDAC patients. Protein kinase G (PKG) conducts the interlude of cGMP signaling which is important for healthy as well as for cancer cells. DT3 is a specific inhibitor of PKG, and it...
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Background: Chemoradioimmunotherapy of patients with pancreatic adenocarcinoma from the CapRI trial did not show any benefit of interferon-α in addition to a 5-fluorouracil (5FU)-based treatment. The aim of this study was to identify immunological parameters in patients from this trial to be used for predictive and/or prognostic purposes. Methods...
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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 cor...
Article
B7-H1 regulatory protein, a member of the B7-H family, plays a crucial role in the modulation of immune response in healthy steady-state conditions as well as in different pathologies. B7-H1 knockout mice represent an important model to elucidate further molecular and cellular mechanisms involved, among others, in autoimmunity development and cance...
Article
cAMP and cGMP signaling is important both for normal and cancer cells. This signaling is controlled by adenylyl and guanylyl cyclases and cyclic nucleotide phosphodiesterases. One of the direct targets for cGMP is protein kinase G (PKG). The main aim of this work was to investigate cGMP and PKG signaling in pancreatic adenocarcinoma (PDAC) cells. T...
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The cytokine interferon-α (IFNα) belongs to the group of type I interferons already used in cancer therapy. This drug possesses radio- and chemo-sensitizing, and shows anti-angiogenic properties. Cancer stem cells (CSC) are a unique population of tumor cells that initiate secondary tumors, and are responsible for metastasis formation. Patients with...
Article
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the comp...
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Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combina...
Article
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. In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. Therefore, new treatment options are urgently nee...
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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of malignancy. Via a broad stimulation of the immune system, PDAC activates both antitumor immune responses and immunosuppressive mechanisms. We propose that new immunotherapeutic strategies for the management of PDAC should be designed to specifically neutralize the immunosuppre...
Article
Phosphodiesterase 5 (PDE5) is a pharmacological target in erectile dysfunction, pulmonary hypertension and in other indications. In tumor-bearing mice an inhibition of PDE5 with sildenafil prolongs survival of the animals through the augmentation of antitumor immunity, indicating the immunomodulatory properties of this drug. Effects of sildenafil o...
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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 o...
Article
Reactive oxygen species (ROS) are a group of highly reactive chemicals under tight control of intracellular antioxidants. The balance in oxidation-antioxidation is essential for maintaining normal cell functions, and any imbalance could lead to a wide range of diseases including cancer. The intracellular level of ROS is generally elevated in cancer...
Article
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 gr...
Article
Reactive oxygen species (ROS) is a group of highly reactive oxygen-containing chemicals. ROS are essential for various biological functions, including cell survival and growth, proliferation and differentiation. At the same time ROS production is connected to a number of disorders, such as chronic inflammation, age-related diseases and cancers. In...
Article
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, unti...
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Blood endothelial cells (ECs) act as gatekeepers to coordinate the extravasation of different T cell subpopulations. ECs express defined panels of adhesion molecules, facilitating interaction with blood circulating T cells. In addition to the mere adhesion, this cellular interaction between ECs and transmigrating T cells may also provide signals th...
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Regulatory T (Treg) cells suppress the sensitization phase of experimental contact hypersensitivity (CHS) reactions when injected before hapten application. Our aim was to analyze the mechanisms by which Treg cells suppress the sensitization phase of CHS reactions. Treg cells were labeled with different fluorescent dyes and injected into naive mice...
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Regulatory molecules of the B7-H-family expressed by DC are important for immune homeostasis, but their regulation is largely unknown. When investigating the pathways regulating B7-H1 expression in monocyte-derived DC (MoDC), freshly isolated myeloid DC (mDC) and plasmacytoid DC, respectively, we showed that in MoDC and mDC B7-H1 expression was upr...
Article
During extracorporeal photophoresis (ECP), peripheral blood mononuclear cells are treated with DNA-intercalating agents and irradiated with ultraviolet light. This procedure exerts immunosuppressive effects, most likely mediated by regulatory T cells (Treg). However, the underlying mechanisms are not clear yet. In our study, we investigated the eff...
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Among antigen-presenting cells (APCs), dendritic cells as well as monocytes acquire immunostimulatory capacity only after appropriate maturation. Therefore, blockade of the maturation/activation results in a steady state or alternatively activated phenotype, which induces tolerance rather than immunity. Functional analyses revealed recently that st...
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The aim of this study was to investigate whether depletion of CD4(+)CD25(+) 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 ce...
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The mechanisms that induce and control the alloimmune inflammation of graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (allo-SCT) are still incompletely understood. In the murine system, GvHD can be suppressed by CD4(+)CD25(+) regulatory T cells (TREG), which are generally involved in the suppression of inflammatory react...
Article
CD4+CD25+ regulatory T cells (T(REG)) are engaged in the regulation of murine and human immune responses as well as graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation. Despite their suppression of GvHD they do not impair graft-versus-tumor activity in the mouse, which makes T(REG) especially attractive candidates for cellul...

Citations

... By inducing miR-194-5p (targeting the B7-H1 gene) and inhibiting miR-155-5p expression, SFN attenuates the phosphorylation of STAT3 in dendritic cells. The inhibition of JAK/STAT3 leads to the downregulation of B7-H1 expression, thereby promoting the activation of T cells [48]. ...
... that CAFs expressed high levels of NT5E mRNA (Fig. 6F). NT5E encodes the ecto-5′-nucleotidase CD73 which converts adenosine monophosphate (AMP) to adenosine and is thereby known to contribute to immune suppression by inducing regulatory and anergic T cell responses [23,24]. CAFs are a major site of CD73 expression and mediate T cell suppression in colorectal cancer [25]. ...
... Besides the endogenous microRNA deregulation observed in CRC, there is an interesting debate in recent literature on exogenous microRNAs found in edible sources and whether these could be transferred via the oral route, withstand digestion and even regulate expression of human genes in a "cross-species" manner [7][8][9][10]. Some reports challenge these findings [11][12][13][14][15] whereas a number of other studies confirmed that, in contrast to the general conviction, some exogenous miRNAs appear to be absorbed in biologically meaningful amounts from nutritionally relevant doses from plants [16] and animals [17,18] and affect gene expression in various tissues in humans [19]. Even though evidence of transfer of miRNAs from the diet to the blood is still inconclusive, some miRNAs have been shown to be resistant during digestion and to reach the enterocytes [20]. ...
... Bromodomain and extraterminal domain inhibitors (BETI) (Bian et al., 2019), daunorubicin (Michel et al., 2018), gemcitabine (Conroy et al., 2018), sulforaphane (Georgikou et al., 2020), doxorubicin , and tumor necrosis factor-related signaling apoptosis-inducing ligand (TRAIL) are commonly used in pancreatic cancer therapy and chemoresistance is often developed during the chemotherapy. Quercetin exhibits cytotoxicity to pancreatic cancer cells at the concentrations from 5 to 100 μM, and may sensitize pancreatic cancer cells to these chemotherapeutic agents ( (Pham et al., 2019). ...
... Recent studies have identified adenosine, a purine nucleoside, as a novel effector molecule of MDSCs. Extracellular ATP or ADP is hydrolyzed by CD39 (nucleoside triphosphate diphosphohydrolase) into AMP, which is in turn cleaved by CD73 (ecto-5'-nucleotidase) into adenosine (27). Both CD39 and CD73 are expressed by MDSCs from tumor-bearing mice and cancer patients, suggesting that MDSCs are capable of producing adenosine (28)(29)(30). ...
... Such asymmetric distribution has been observed in cancer before (e.g., 62) and suggests an actively regulated secretion of miRNA molecules from cells. Four of the other five molecules-miR-122-5p, miR-205-5p, miR-326, miR-365a-3p-are known to be associated with PDAC (63)(64)(65)(66). No such link has been reported for miR-154-5p, but it has been found to act as a tumor suppressor in several tumor entities (67). ...
... Particularly, the so-called immune checkpoint molecules (ICPM) attract an enormous attention of scientists and clinicians due to the fact that immunotherapy using antibody or inhibitors targeting these molecules could demonstrate spectacular clinical responses. 1 These exciting results led to the approval of antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1, B7-H1) for treatment of patients with melanoma, non-small cell lung cancer, and renal cell carcinoma. 2 Unfortunately, only restricted cohorts of patients benefit from these treatments probably due to an intricate network of strong immunosuppression. ...
... It was revealed that transcription factor STAT3 was promoted significantly, which might regulate the PD-L1 expression and M2 polarization. 32,35 For further verification, the expression of p-MerTK/ MerTK, p-p38/p38, and p-STAT3/STAT3 was detected after 15, 30, 60, 120, and 240 min of efferocytosis. With MerTK KD, we found that the phosphorylation of p38 (p-p38/p38) and STAT3 (p-STAT3/STAT3) was inhibited significantly (Figure 4c-e), as well as the attenuated expression of PD-L1 and Arg1 (Figure 4c,f,g). ...
... For that purpose, the ovarian-cancer spheroid model directly derived from an individual patient tumor was used for drug screening. This 3D microtumor model closely reflects the tumor heterogeneity and architecture of the original tumor tissues [12,13], and is predictive for the drug response of the individual patient [14]. In addition, the heterogeneity of protein biomarker expression was immunohistochemically analyzed in corresponding tumor lesions to identify promising targets for molecular therapy. ...
... It is widely accepted that chronic exposure to tobacco smoke and/or occupational carcinogens generates a production of reactive oxygen species (ROS) which induce genotoxic effects through CYP1A1-mediated metabolites and oxidative stress pathways [7]. A large number of studies have shown that oxidative stress plays an important role in carcinogenesis [8][9][10][11][12]. Namely, long-term accumulation of ROS leads to damage of all types of cellular and extracellular macromolecules, including DNA [13,14]. ...