Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. Over the recent years ...IO therapy has been broadly integrated into the first-line setting of non-oncogene driven NSCLC, either in combination with chemotherapy, or in selected patients with PD-L1
expression as monotherapy. Still, a significant proportion of patients suffer from disease progression. A better understanding of resistance mechanisms depicts a central goal to avoid or overcome IO resistance and to improve patient outcome.We here review major cellular and molecular pathways within the tumor microenvironment (TME) that may impact the evolution of IO resistance. We summarize upcoming treatment options after IO resistance including novel IO targets (e.g. RIG-I, STING) as well as interesting combinational approaches such as IO combined with anti-angiogenic agents or metabolic targets (e.g. IDO-1, adenosine signaling, arginase). By discussing the fundamental mode of action of IO within the TME, we aim to understand and manage IO resistance and to seed new ideas for effective therapeutic IO concepts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The tumor microenvironment (TME) plays a central role in cancer development and progression. It represents a complex network of cancer cell (sub-)clones and a variety of stromal cell types. Recently, ...new technology platforms shed light on the cellular composition of the TME at very high resolution and identified a complex landscape of multi-lineage immune cells (e.g., T and B lymphocytes, myeloid cells, and dendritic cells), cancer associated fibroblasts (CAF) and tumor endothelial cells (TECs). A growing body of evidence suggests that metabolically, genetically and on their transcriptomic profile TECs exhibit unique phenotypic and functional characteristics when compared to normal endothelial cells (NECs). Furthermore, the functional role of TECs is multifaceted as they are not only relevant for promoting tumor angiogenesis but have also evolved as key mediators of immune regulation in the TME. Regulatory mechanisms are complex and profoundly impact peripheral immune cell trafficking into the tumor compartment by acting as major gatekeepers of cellular transmigration. Moreover, TECs are associated with T cell priming, activation and proliferation by acting as antigen-presenting cells themselves. TECs are also essential for the formation of tertiary lymphoid structures (TLS) within the tumor, which have recently been associated with treatment response to checkpoint antibody therapy. Further essential characteristics of TECs compared to NECs are their high proliferative potential as well as greatly altered gene expression profile (e.g., upregulation of pro-angiogenic, extracellular matrix remodeling, and stemness genes), which results in enhanced secretion of immunomodulatory cytokines and altered cell-surface receptors e.g., major histocompatibility complex (MHC) and immune checkpoints. The TEC phenotype may be rooted in an aggressive tumor micro-milieu based on cellular stress
via
hypoxia and reactive oxygen species (ROS).
Vice versa
TECs might modulate TME immunogenicity thereby fostering cancer-associated immune suppression. This review aims to elucidate the currently emergent pathophysiological aspects of TECs with a particular focus on their potential role as regulators of immune cell function in the TME. It is a main future challenge to deeply characterize the phenotypic and functional profile of TECs to illuminate their complex role within the TME. The ultimate goal is the identification of TEC-specific drug targets to improve cancer (immuno-)therapy.
The Janus kinase (JAK)–inhibitor ruxolitinib decreases constitutional symptoms and spleen size of myelofibrosis (MF) patients by mechanisms distinct from its anticlonal activity. Here we investigated ...whether ruxolitinib affects dendritic cell (DC) biology. The in vitro development of monocyte-derived DCs was almost completely blocked when the compound was added throughout the differentiation period. Furthermore, when applied solely during the final lipopolysaccharide-induced maturation step, ruxolitinib reduced DC activation as demonstrated by decreased interleukin-12 production and attenuated expression of activation markers. Ruxolitinib also impaired both in vitro and in vivo DC migration. Dysfunction of ruxolitinib-exposed DCs was further underlined by their impaired induction of allogeneic and antigen-specific T-cell responses. Ruxolitinib-treated mice immunized with ovalbumin (OVA)/CpG induced markedly reduced in vivo activation and proliferation of OVA-specific CD8+ T cells compared with vehicle-treated controls. Finally, using an adenoviral infection model, we show that ruxolitinib-exposed mice exhibit delayed adenoviral clearance. Our results demonstrate that ruxolitinib significantly affects DC differentiation and function leading to impaired T-cell activation. DC dysfunction may result in increased infection rates in ruxolitinib-treated patients. However, our findings may also explain the outstanding anti-inflammatory and immunomodulating activity of JAK inhibitors currently used in the treatment of MF and autoimmune diseases.
•The JAK-inhibitor ruxolitinib affects dendritic cell differentiation, phenotype, and function leading to impaired T-cell activation.
Cancer patients frequently use complementary medicine. Curcumin (CUR) and its derivates (from the extract of
L.) represent some of the most frequently used ones, having a long history in traditional ...Asian medicine. CUR was demonstrated, both in vitro and in vivo, to have significant anti-inflammatory effects, thus potentially counteracting cancer-promoting inflammation, which is a hallmark of cancer. CUR modulate a plethora of signaling pathways in cancer cells, comprising the NF-κB (nuclear factor k-light-chain-enhancer of activated B cells), the JAK/STAT (Janus-Kinase/Signal Transducers and Activators of Transcription), and the TGF-β (transforming growth factor-β) pathways. Furthermore, CUR confers properties of electron receptors, which destabilize radical oxygen species (ROS), explaining its antioxidant and anti-apopototic effects. Although CUR has a low bioavailability, its role in advanced cancer treatment and supportive care was addressed in numerous clinical trials. After promising results in phase I⁻II trials, multiple phase III trials in different indications are currently under way to test for direct anti-cancer effects. In addition, CUR exerts beneficial effects on cancer treatment-related neurotoxcity, cardiotoxicity, nephrotoxicity, hemato-toxicity, and others. More efficient galenic formulations are tested to optimze CUR's usability in cancer treatment. This review should provide a comprehensive overview of basic science, and pre-clinical and clinical data on CUR in the field of oncology.
Abstract
Refractive power measurements serve as the primary quality standard in the automotive glazing industry. In the light of autonomous driving new optical metrics are becoming more and more ...popular for specifying optical quality requirements for the windshield. Nevertheless, the link between those quantities and the refractive power needs to be established in order to ensure a holistic requirement profile for the windshield. As a consequence, traceable high-resolution refractive power measurements are still required for the glass quality assessment. Standard measurement systems using Moiré patterns for refractive power monitoring in the automotive industry are highly resolution limited, wherefore they are insufficient for evaluating the camera window area. Consequently, there is a need for more sophisticated refractive power measurement systems that provide a higher spatial resolution. In addition, a calibration procedure has to be developed in order to guarantee for the comparability of the measurement results. For increasing the resolution, a measurement setup based on an auto-correlation algorithm is tested in this paper. In order to benchmark the proposed high-resolution refractive power measurement technique, a novel laser-based setup has been realized in the Volkswagen Laser Laboratory as a reference method tuned for high-accuracy measurements. Furthermore, a calibration procedure is established by using a single reference lens with a nominal refractive power of
100
k
m
−
1
. For the calibration of the entire measurement range of the system, the lens is tilted by an inclination angle orthogonal to the optical axis. The effective refractive power is then given by the Kerkhof model. By adopting the measurement and calibration procedure presented in this paper, glass suppliers in the automotive industry will be able to detect relevant manufacturing defects within the camera window area more accurately paving the way for a holistic quality assurance of the windshield for future advanced driver-assistance system (ADAS) functionalities. Concurrently, the traceability of the measurement results is ensured by establishing a calibration chain based on a single reference lens, which is traced back to international standards.
Ruxolitinib is a small-molecule inhibitor of the JAK kinases, which has been approved for the treatment of myelofibrosis, a rare myeloproliferative neoplasm (MPN), but clinical trials are also being ...conducted in inflammatory-driven solid tumors. Increased infection rates have been reported in ruxolitinib-treated patients, and natural killer (NK) cells are immune effector cells known to eliminate both virus-infected and malignant cells. On this basis, we sought to compare the effects of JAK inhibition on human NK cells in a cohort of 28 MPN patients with or without ruxolitinib treatment and 24 healthy individuals. NK cell analyses included cell frequency, receptor expression, proliferation, immune synapse formation, and cytokine signaling. We found a reduction in NK cell numbers in ruxolitinib-treated patients that was linked to the appearance of clinically relevant infections. This reduction was likely due to impaired maturation of NK cells, as reflected by an increased ratio in immature to mature NK cells. Notably, the endogenous functional defect of NK cells in MPN was further aggravated by ruxolitinib treatment. In vitro data paralleled these in vivo results, showing a reduction in cytokine-induced NK cell activation. Further, reduced killing activity was associated with an impaired capacity to form lytic synapses with NK target cells. Taken together, our findings offer compelling evidence that ruxolitinib impairs NK cell function in MPN patients, offering an explanation for increased infection rates and possible long-term side effects associated with ruxolitinib treatment.
Abstract
Background
Crosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic ...avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME.
Methods
TEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell–cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model.
Results
Compared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro.
Conclusions
Overall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa.
Graphical Abstract
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
9.
The Biology of Classic Hairy Cell Leukemia Bohn, Jan-Paul; Salcher, Stefan; Pircher, Andreas ...
International journal of molecular sciences,
08/2021, Letnik:
22, Številka:
15
Journal Article
Recenzirano
Odprti dostop
Classic hairy cell leukemia (HCL) is a rare mature B-cell malignancy associated with pancytopenia and infectious complications due to progressive infiltration of the bone marrow and spleen. Despite ...tremendous therapeutic advances achieved with the implementation of purine analogues such as cladribine into clinical practice, the culprit biologic alterations driving this fascinating hematologic disease have long stayed concealed. Nearly 10 years ago, BRAF V600E was finally identified as a key activating mutation detectable in almost all HCL patients and throughout the entire course of the disease. However, additional oncogenic biologic features seem mandatory to enable HCL transformation, an open issue still under active investigation. This review summarizes the current understanding of key pathogenic mechanisms implicated in HCL and discusses major hurdles to overcome in the context of other BRAF-mutated malignancies.
This study was stimulated by the clinical observation of a rapid response of a chilblain lupus patient to treatment with JAK1/2‐kinase inhibitor ruxolitinib. We investigated the in vivo expression of ...phospho‐JAK2 in CLE skin samples as well as the immunomodulatory in vitro effect of ruxolitinib in cultured immortalized keratinocytes and in a 3D human epidermis model (epiCS). Our results demonstrate that ruxolitinib significantly decreases the production of CLE‐typical cytokines (CXCL10, CXCL9, MxA) and might be a promising drug for future clinical studies in patients with CLE and related autoimmune skin diseases.
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