Publications by authors named "Marc Schmitz"

118 Publications

Two Be or Not Two Be: The Nuclear Autoantigen La/SS-B Is Able to Form Dimers and Oligomers in a Redox Dependent Manner.

Int J Mol Sci 2021 Mar 25;22(7). Epub 2021 Mar 25.

Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01328 Dresden, Germany.

According to the literature, the autoantigen La is involved in Cap-independent translation. It was proposed that one prerequisite for this function is the formation of a protein dimer. However, structural analyses argue against La protein dimers. Noteworthy to mention, these structural analyses were performed under reducing conditions. Here we describe that La protein can undergo redox-dependent structural changes. The oxidized form of La protein can form dimers, oligomers and even polymers stabilized by disulfide bridges. The primary sequence of La protein contains three cysteine residues. Only after mutation of all three cysteine residues to alanine La protein becomes insensitive to oxidation, indicating that all three cysteines are involved in redox-dependent structural changes. Biophysical analyses of the secondary structure of La protein support the redox-dependent conformational changes. Moreover, we identified monoclonal anti-La antibodies (anti-La mAbs) that react with either the reduced or oxidized form of La protein. Differential reactivities to the reduced and oxidized form of La protein were also found in anti-La sera of autoimmune patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22073377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036718PMC
March 2021

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer.

Cancers (Basel) 2021 Mar 15;13(6). Epub 2021 Mar 15.

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.

T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8 and Th1-polarized CD4 T cell infiltration is associated with prolonged survival in human pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3 T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13061297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998134PMC
March 2021

Tumor-infiltrating plasmacytoid dendritic cells are associated with survival in human colon cancer.

J Immunother Cancer 2021 Mar;9(3)

Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany

Background: Plasmacytoid dendritic cells (pDCs) play a key role in the induction and maintenance of antitumor immunity. Conversely, they can act as tolerogenic DCs by inhibiting tumor-directed immune responses. Therefore, pDCs may profoundly influence tumor progression. To gain novel insights into the role of pDCs in colon cancer, we investigated the frequency and clinical relevance of pDCs in primary tumor tissues from patients with colon cancer with different clinicopathological characteristics.

Methods: Immunohistochemical stainings were performed to explore the frequency of tumor-infiltrating BDCA-2 pDCs in patients with colon cancer. Statistical analyses were conducted to determine an association between the pDC density and clinicopathological characteristics of the patients. Furthermore, we used multiplex immunofluorescence stainings to evaluate the localization and phenotype of pDCs in stroma and tertiary lymphoid structures (TLS) of colon cancer tissues.

Results: An increased density of infiltrating pDCs was associated with lower Union for International Cancer Control (UICC) stages. Furthermore, a higher pDC frequency was significantly correlated with increased progression-free and overall survival of patients with colon cancer. Moreover, a lower number of coloncancer-infiltrating pDCs was significantly and independently linked to worse prognosis. In addition, we found that a proportion of pDCs shows a nuclear expression of the transcription factor interferon regulatory factor 7 (IRF7), which is characteristic for an activated phenotype. In various tumor stroma regions, IRF7 pDCs were located in the neighborhood of granzyme B-expressing CD8 T cells. Moreover, pDCs were identified as a novel component of the T cell zone of colon cancer-associated TLS, which are major regulators of adaptive antitumor immunity. A proportion of TLS-associated pDCs displayed a nuclear IRF7 expression and was preferentially located close to CD4 T cells.

Conclusions: These results indicate that higher densities of tumor-infiltrating pDCs are associated with prolonged survival of patients with colon cancer. Moreover, colon cancer-infiltrating pDCs may represent a novel prognostic factor. The colocalization of activated pDCs and T cells in tumor stroma and within TLS may contribute to the correlation between higher pDC densities and better prognosis. In addition, our findings may have implications for the design of novel immunotherapeutic strategies that are based on targeting colon cancer-infiltrating pDCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001813DOI Listing
March 2021

Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update.

Front Cell Dev Biol 2021 9;9:637725. Epub 2021 Feb 9.

Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.

Mesenchymal stromal cells (MSCs) are characterized by an extraordinary capacity to modulate the phenotype and functional properties of various immune cells that play an essential role in the pathogenesis of inflammatory disorders. Thus, MSCs efficiently impair the phagocytic and antigen-presenting capacity of monocytes/macrophages and promote the expression of immunosuppressive molecules such as interleukin (IL)-10 and programmed cell death 1 ligand 1 by these cells. They also effectively inhibit the maturation of dendritic cells and their ability to produce proinflammatory cytokines and to stimulate potent T-cell responses. Furthermore, MSCs inhibit the generation and proinflammatory properties of CD4 T helper (Th)1 and Th17 cells, while they promote the proliferation of regulatory T cells and their inhibitory capabilities. MSCs also impair the expansion, cytokine secretion, and cytotoxic activity of proinflammatory CD8 T cells. Moreover, MSCs inhibit the differentiation, proliferation, and antibody secretion of B cells, and foster the generation of IL-10-producing regulatory B cells. Various cell membrane-associated and soluble molecules essentially contribute to these MSC-mediated effects on important cellular components of innate and adaptive immunity. Due to their immunosuppressive properties, MSCs have emerged as promising tools for the treatment of inflammatory disorders such as acute graft-versus-host disease, graft rejection in patients undergoing organ/cell transplantation, and autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.637725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900158PMC
February 2021

T Cell Mediated Conversion of a Non-Anti-La Reactive B Cell to an Autoreactive Anti-La B Cell by Somatic Hypermutation.

Int J Mol Sci 2021 Jan 26;22(3). Epub 2021 Jan 26.

Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 03128 Dresden, Germany.

Since the first description of nuclear autoantigens in the late 1960s and early 1970s, researchers, including ourselves, have found it difficult to establish monoclonal antibodies (mabs) against nuclear antigens, including the La/SS-B (Sjögrens' syndrome associated antigen B) autoantigen. To date, only a few anti-La mabs have been derived by conventional hybridoma technology; however, those anti-La mabs were not bona fide autoantibodies as they recognize either human La specific, cryptic, or post-translationally modified epitopes which are not accessible on native mouse La protein. Herein, we present a series of novel murine anti-La mabs including truly autoreactive ones. These mabs were elicited from a human La transgenic animal through adoptive transfer of T cells from non-transgenic mice immunized with human La antigen. Detailed epitope and paratope analyses experimentally confirm the hypothesis that somatic hypermutations that occur during T cell dependent maturation can lead to autoreactivity to the nuclear La/SS-B autoantigen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22031198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865296PMC
January 2021

PD-1 Expression by Lymph Node and Intratumoral Regulatory T Cells Is Associated with Lymph Node Metastasis in Pancreatic Cancer.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a mostly immunosuppressive microenvironment. Tumor-draining lymph nodes (TDLN) are a major site for priming of tumor-reactive T cells and also tumor metastasis. However, the phenotype and function of T cells in TDLNs from PDAC patients is unknown. In this study, lymph nodes from the pancreatic head (PH), the hepatoduodenal ligament (HDL) and the interaortocaval (IAC) region were obtained from 25 patients with adenocarcinoma of the pancreatic head. Additionally, tumors and matched blood were analyzed from 16 PDAC patients. Using multicolor flow cytometry, we performed a comprehensive analysis of T cells. CD4 T cells were the predominant T cell subset in PDAC-draining lymph nodes. Overall, lymph node CD4 and CD8 T cells had a similar degree of activation, as measured by CD69, inducible T cell co-stimulator (ICOS) and CD137 (4-1BB) expression and interferon-γ (IFNγ) secretion. Expression of the inhibitory receptor programmed death 1 (PD-1) by lymph node and tumor-infiltrating regulatory T cells (Tregs) correlated with lymph node metastasis. Collectively, Treg cells and PD-1 are two relevant components of the immunosuppressive network in PDAC-draining lymph nodes and may be particularly attractive targets for combinatorial immunotherapeutic strategies in selected patients with node-positive PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12102756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599971PMC
September 2020

Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141 dendritic cells to activate naïve and memory WT1-specific CD8 T cells.

Clin Transl Immunology 2020 12;9(6):e1141. Epub 2020 Jun 12.

Cancer Immunotherapies Laboratory Mater Research Institute - The University of Queensland Translational Research Institute Woolloongabba Australia 4102 Australia.

Objectives: Vaccines that prime Wilms' tumor 1 (WT1)-specific CD8 T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141 dendritic cells (DCs). The C-type lectin-like receptor CLEC9A is expressed exclusively by CD141 DCs and regulates CD8 T-cell responses. We developed a new vaccine comprising a human anti-CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141 DCs and activate naïve and memory WT1-specific CD8 T cells.

Methods: WT1 was genetically fused to antibodies specific for human CLEC9A, DEC-205 or β-galactosidase (untargeted control). Activation of WT1-specific CD8 T-cell lines following cross-presentation by CD141 DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1-specific CD8 T cells, were used to investigate naïve WT1-specific CD8 T-cell priming.

Results: The CLEC9A-WT1 vaccine promoted cross-presentation of WT1 epitopes to CD8 T cells and mediated priming of naïve CD8 T cells more effectively than the DEC-205-WT1 and untargeted control-WT1 vaccines.

Conclusions: Delivery of WT1 to CD141 DCs via CLEC9A stimulates CD8 T cells more potently than either untargeted delivery or widespread delivery to all Ag-presenting cells via DEC-205, suggesting that cross-presentation by CD141 DCs is sufficient for effective CD8 T-cell priming in humans. The CLEC9A-WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cti2.1141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292901PMC
June 2020

Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia.

Sci Transl Med 2020 06;12(546)

John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham NG11 8NS, UK.

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the complexity of the immune architecture of AML at high resolution and assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease classes and revealed critical differences in immune gene expression across age groups and molecular disease subtypes. Interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles provides insights into the immuno-biology of AML and could inform the delivery of personalized immunotherapies to IFN-γ-dominant AML subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aaz0463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427158PMC
June 2020

UniCAR T cell immunotherapy enables efficient elimination of radioresistant cancer cells.

Oncoimmunology 2020 5;9(1):1743036. Epub 2020 Apr 5.

Department of Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.

Induction or selection of radioresistant cancer (stem) cells following standard radiotherapy is presumably one of the major causes for recurrence of metastatic disease. One possibility to prevent tumor relapse is the application of targeted immunotherapies including, e.g., chimeric antigen receptor (CAR) T cells. In light of long-term remissions, it is highly relevant to clarify whether radioresistant cancer cells are susceptible to CAR T cell-mediated killing. To answer this question, we evaluated the anti-tumor activity of the switchable universal chimeric antigen receptor (UniCAR) system against highly radioresistant head and neck squamous cell carcinoma cells both and . Following specific UniCAR T cell engagement via EGFR or CD98 target modules, T cell effector mechanisms were induced including secretion of pro-inflammatory cytokines, up-regulation of granzyme B and perforin, as well as T cell proliferation. CD98- or EGFR-redirected UniCAR T cells further possess the capability to efficiently lyse radioresistant tumor cells. Observed anti-tumor effects were comparable to those against the radiosensitive parental cell lines. Finally, redirected UniCAR T cells significantly inhibited the growth of radioresistant cancer cells in immunodeficient mice. Taken together, our obtained data underline that the UniCAR system is able to overcome radioresistance. Thus, it represents an attractive technology for the development of combined radioimmunotherapeutic approaches that might improve the outcome of patients with metastatic radioresistant tumor diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1743036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219270PMC
April 2020

Marine biomaterials: Biomimetic and pharmacological potential of cultivated Aplysina aerophoba marine demosponge.

Mater Sci Eng C Mater Biol Appl 2020 Apr 17;109:110566. Epub 2019 Dec 17.

Institute of Electronics and Sensor Materials, Technische Universität Bergakademie Freiberg, Freiberg 09599, Germany. Electronic address:

Marine demosponges of the Verongiida order are considered a gold-mine for bioinspired materials science and marine pharmacology. The aim of this work was to simultaneously isolate selected bromotyrosines and unique chitinous structures from A. aerophoba and to propose these molecules and biomaterials for possible application as antibacterial and antitumor compounds and as ready-to-use scaffolds for cultivation of cardiomyocytes, respectively. Among the extracted bromotyrosines, the attention has been focused on aeroplysinin-1 that showed interesting unexpected growth inhibition properties for some Gram-negative clinical multi-resistant bacterial strains, such as A. baumannii and K. pneumoniae, and on aeroplysinin-1 and on isofistularin-3 for their anti-tumorigenic activity. For both compounds, the effects are cell line dependent, with significant growth inhibition activity on the neuroblastoma cell line SH-SY5Y by aeroplysinin-1 and on breast cancer cell line MCF-7 by isofistularin-3. In this study, we also compared the cultivation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) on the A. aerophoba chitinous scaffolds, in comparison to chitin structures that were pre-coated with Geltrex™, an extracellular matrix mimetic which is used to enhance iPSC-CM adhesion. The iPSC-CMs on uncoated and pure chitin structures started contracting 24 h after seeding, with comparable behaviour observed on Geltrex-coated cell culture plates, confirming the biocompatibility of the sponge biomaterial with this cell type. The advantage of A. aerophoba is that this source organism does not need to be collected in large quantities to supply the necessary amount for further pre-clinical studies before chemical synthesis of the active compounds will be available. A preliminary analysis of marine sponge bioeconomy as a perspective direction for application of biomaterials and secondary bioactive metabolites has been finally performed for the first time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msec.2019.110566DOI Listing
April 2020

Influence of phase of respiratory cycle on ultrasound imaging of deep abdominal muscle thickness.

Musculoskelet Sci Pract 2020 04 27;46:102105. Epub 2019 Dec 27.

REVAL Rehabilitation Research Center, Faculty of Rehabilitation Sciences, Hasselt University, 3590, Diepenbeek, Belgium. Electronic address:

Background: It is difficult to evaluate the transversus abdominis (TrA) and internal oblique (IO) due to their dual role in both trunk control and breathing.

Objectives: To investigate whether TrA and IO thickness as measured by ultrasound differs across the respiratory cycle in upright standing.

Design: Observational study.

Methods: Thickness of TrA and IO was measured with ultrasound in 67 subjects in upright standing. Measures were performed 3 times and by 2 assessors, at the end of relaxed expiration, at the end of a full inspiration, and at the end of full expiration. Differences were assessed by ANOVA. Intra- and inter-rater reliability (of a single measure and the average of 3 measures) were assessed by intra-class correlation (ICC).

Results: Thickness of the TrA and IO was higher at full expiration than at the end of relaxed expiration (p < 0.001), and in turn compared to at full inspiration (p < 0.001). Intra-rater reliability was excellent at all respiratory phases (ICC 0.76-0.87). Whereas inter-rater reliability for a single measure was only fair to good for TrA (ICC 0.52-0.71) and good to excellent for IO (ICC 0.61-0.78), the inter-rater reliability of the average was excellent at all respiratory phases (ICC 0.75-0.90).

Conclusions: Thickness of TrA and IO increases when lung volume decreases. The intra- and inter-rater reliability of an average measure were excellent at the end of relaxed expiration, full inspiration and full expiration. This provides new opportunities to evaluate the deep abdominal muscles, and their role in respiration, in a physiotherapeutic setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msksp.2019.102105DOI Listing
April 2020

Characteristics of Tumor-Infiltrating Lymphocytes Prior to and During Immune Checkpoint Inhibitor Therapy.

Front Immunol 2020 4;11:364. Epub 2020 Mar 4.

Faculty of Medicine Carl Gustav Carus, Institute of Immunology, TU Dresden, Dresden, Germany.

The tumor immune contexture plays a major role for the clinical outcome of patients. High densities of CD45RO T helper 1 cells and CD8 T cells are associated with improved survival of patients with various cancer entities. In contrast, a higher frequency of tumor-infiltrating M2 macrophages is correlated with poor prognosis. Recent studies provide evidence that the tumor immune architecture also essentially contributes to the clinical efficacy of immune checkpoint inhibitor (CPI) therapy in patients. Pretreatment melanoma samples from patients who experienced a clinical response to anti-programmed cell death protein 1 (PD-1) treatment show higher densities of infiltrating CD8 T cells compared to samples from patients that progressed during therapy. Anti-PD-1 therapy results in an increased density of tumor-infiltrating T lymphocytes in treatment responders. In addition, elevated frequencies of melanoma-infiltrating TCF7CD8 T cells are correlated with beneficial clinical outcome of anti-PD-1-treated patients. In contrast, a high density of tumor-infiltrating, dysfunctional PD-1CD38 CD8 cells in melanoma patients is associated with anti-PD-1 resistance. Such findings indicate that comprehensive tumor immune contexture profiling prior to and during CPI therapy may lead to the identification of underlying mechanisms for treatment response or resistance, and the design of improved immunotherapeutic strategies. Here, we focus on studies exploring the impact of intratumoral T and B cells at baseline on the clinical outcome of CPI-treated cancer patients. In addition, recent findings demonstrating the influence of CPIs on tumor-infiltrating lymphocytes are summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.00364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064638PMC
March 2021

Bidirectional Crosstalk Between Cancer Stem Cells and Immune Cell Subsets.

Front Immunol 2020 5;11:140. Epub 2020 Feb 5.

Faculty of Medicine Carl Gustav Carus, Institute of Immunology, TU Dresden, Dresden, Germany.

Cancer stem cells (CSCs), also known as tumor-initiating cells, are characterized by an increased capacity for self-renewal, multipotency, and tumor initiation. While CSCs represent only a small proportion of the tumor mass, they significantly account for metastatic dissemination and tumor recurrence, thus making them attractive targets for therapy. Due to their ability to sustain in dormancy, chemo- and radiotherapy often fail to eliminate cancer cells with stemness properties. Recent advances in the understanding of the tumor microenvironment (TME) illustrated the importance of the immune contexture, determining the response to therapy and clinical outcome of patients. In this context, CSCs exhibit special properties to escape the recognition by innate and adaptive immunity and shape the TME into an immunosuppressive, pro-tumorigenic landscape. As CSCs sculpt the immune contexture, the phenotype and functional properties of the tumor-infiltrating immune cells in turn influence the differentiation and phenotype of tumor cells. In this review, we summarize recent studies investigating main immunomodulatory properties of CSCs and their underlying molecular mechanisms as well as the impact of immune cells on cancer cells with stemness properties. A deeper understanding of this bidirectional crosstalk shaping the immunological landscape and determining therapeutic responses will facilitate the improvement of current treatment modalities and the design of innovative strategies to precisely target CSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013084PMC
March 2021

"UniCAR"-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells.

Sci Rep 2020 02 7;10(1):2141. Epub 2020 Feb 7.

Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.

Antigen-specific redirection of immune effector cells with chimeric antigen receptors (CARs) demonstrated high therapeutic potential for targeting cancers of different origins. Beside CAR-T cells, natural killer (NK) cells represent promising alternative effectors that can be combined with CAR technology. Unlike T cells, primary NK cells and the NK cell line NK-92 can be applied as allogeneic off-the-shelf products with a reduced risk of toxicities. We previously established a modular universal CAR (UniCAR) platform which consists of UniCAR-expressing immune cells that cannot recognize target antigens directly but are redirected by a tumour-specific target module (TM). The TM contains an antigen-binding moiety fused to a peptide epitope which is recognized by the UniCAR molecule, thereby allowing an on/off switch of CAR activity, and facilitating flexible targeting of various tumour antigens depending on the presence and specificity of the TM. Here, we provide proof of concept that it is feasible to generate a universal off-the-shelf cellular therapeutic based on UniCAR NK-92 cells targeted to tumours expressing the disialoganglioside GD2 by GD2-specific TMs that are either based on an antibody-derived single-chain fragment variable (scFv) or an IgG4 backbone. Redirected UniCAR NK-92 cells induced specific killing of GD2-expressing cells in vitro and in vivo, associated with enhanced production of interferon-γ. Analysis of radiolabelled proteins demonstrated that the IgG4-based format increased the in vivo half-life of the TM markedly in comparison to the scFv-based molecule. In summary, UniCAR NK-92 cells represent a universal off-the-shelf platform that is highly effective and flexible, allowing the use of different TM formats for specific tumour targeting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-59082-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005792PMC
February 2020

Anti-PD-1 and Novel Combinations in the Treatment of Melanoma-An Update.

J Clin Med 2020 Jan 14;9(1). Epub 2020 Jan 14.

Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.

Until recently, distant metastatic melanoma was considered refractory to systemic therapy. A better understanding of the interactions between tumors and the immune system and the mechanisms of regulation of T-cells led to the development of immune checkpoint inhibitors. This review summarizes the current novel data on the treatment of metastatic melanoma with anti-programmed cell death protein 1 (PD-1) antibodies and anti-PD-1-based combination regimens, including clinical trials presented at major conference meetings. Immune checkpoint inhibitors, in particular anti-PD-1 antibodies such as pembrolizumab and nivolumab and the combination of nivolumab with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab can achieve long-term survival for patients with metastatic melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab were also approved for adjuvant treatment of patients with resected metastatic melanoma. Anti-PD-1 antibodies appear to be well tolerated, and toxicity is manageable. Nivolumab combined with ipilimumab achieves a 5 year survival rate of more than 50% but at a cost of high toxicity. Ongoing clinical trials investigate novel immunotherapy combinations and strategies (e.g., Talimogene laherparepvec (T-VEC), Bempegaldesleukin (BEMPEG), incorporation or sequencing of targeted therapy, incorporation or sequencing of radiotherapy), and focus on poor prognosis groups (e.g., high tumor burden/LDH levels, anti-PD-1 refractory melanoma, and brain metastases).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9010223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019511PMC
January 2020

Reliable isolation of human mesenchymal stromal cells from bone marrow biopsy specimens in patients after allogeneic hematopoietic cell transplantation.

Cytotherapy 2020 01 27;22(1):21-26. Epub 2019 Dec 27.

Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Isolation of mesenchymal stromal cells (MSCs) from pretreated, hematologic patients is challenging. Especially after allogeneic hematopoietic cell transplantation (HCT), standard protocols using bone marrow aspirates fail to reliably recover sufficient cell numbers. Because MSCs are considered to contribute to processes that mainly affect the outcome after transplantation, such as an efficient lymphohematopoietic recovery, extent of graft-versus-host disease as well as the occurrence of leukemic relapse, it is of great clinical relevance to investigate MSC function in this context. Previous studies showed that MSCs can be isolated by collagenase digestion of large bone fragments of hematologically healthy patients undergoing hip replacement or knee surgeries. We have now further developed this procedure for the isolation of MSCs from hematologic patients after allogeneic HCT by using trephine biopsy specimens obtained during routine examinations. Comparison of aspirates and trephine biopsy specimens from patients after allogeneic HCT revealed a significantly higher frequency of clonogenic MSCs (colony-forming unit-fibroblast [CFU-F]) in trephine biopsy specimens (mean, 289.8 ± standard deviation 322.5 CFU-F colonies/1 × 10 total nucleated cells versus 4.2 ± 9.9; P < 0.0001). Subsequent expansion of functional MSCs isolated from trephine biopsy specimen was more robust and led to a significantly higher yield compared with control samples expanded from aspirates (median, 1.6 × 10; range, 0-2.3 × 10 P0 MSCs versus 5.4 × 10; range, 0-8.9 × 10; P < 0.0001). Using trephine biopsy specimens as MSC source facilitates the investigation of various clinical questions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcyt.2019.10.012DOI Listing
January 2020

A new synthetic toll-like receptor 1/2 ligand is an efficient adjuvant for peptide vaccination in a human volunteer.

J Immunother Cancer 2019 11 15;7(1):307. Epub 2019 Nov 15.

Department of Immunology, Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany.

Background: We previously showed that the bacterial lipopeptide PamCys-Ser-Ser, meanwhile established as a toll-like receptor (TLR) 1/2 ligand, acts as a strong adjuvant for the induction of virus specific CD8 T cells in mice, when covalently coupled to a synthetic peptide.

Case Presentation: We now designed a new water-soluble synthetic PamCys-derivative, named XS15 and characterized it in vitro by a TLR2 NF-κB luciferase reporter assay. Further, the capacity of XS15 to activate immune cells and stimulate peptide-specific CD8 T and NK cells by 6-sulfo LacNAc monocytes was assessed by flow cytometry as well as cytokine induction using immunoassays. The induction of a functional immune response after vaccination of a volunteer with viral peptides was assessed by ELISpot assay and flow cytometry in peripheral blood cells and infiltrating cells at the vaccination site, as well as by immunohistochemistry and imaging. XS15 induced strong ex vivo CD8 and T1 CD4 responses in a human volunteer upon a single injection of XS15 mixed to uncoupled peptides in a water-in-oil emulsion (Montanide™ ISA51 VG). A granuloma formed locally at the injection site containing highly activated functional CD4 and CD8 effector memory T cells. The total number of vaccine peptide-specific functional T cells was experimentally assessed and estimated to be 3.0 × 10 in the granuloma and 20.5 × 10 in peripheral blood.

Conclusion: Thus, in one volunteer we show a granuloma forming by peptides combined with an efficient adjuvant in a water-in-oil-emulsion, inducing antigen specific T cells detectable in circulation and at the vaccination site, after one single vaccination only. The ex vivo T cell responses in peripheral blood were detectable for more than one year and could be strongly boosted by a second vaccination. Hence, XS15 is a promising adjuvant candidate for peptide vaccination, in particular for tumor peptide vaccines in a personalized setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40425-019-0796-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858783PMC
November 2019

A theranostic PSMA ligand for PET imaging and retargeting of T cells expressing the universal chimeric antigen receptor UniCAR.

Oncoimmunology 2019;8(11):1659095. Epub 2019 Sep 7.

Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.

Chimeric antigen receptor (CAR) T cells have shown impressive therapeutic potential. Due to the lack of direct control mechanisms, therapy-related adverse reactions including cytokine release- and tumor lysis syndrome can even become life-threatening. In case of target antigen expression on non-malignant cells, CAR T cells can also attack healthy tissues. To overcome such side effects, we have established a modular CAR platform termed UniCAR: UniCAR T cells per se are inert as they recognize a peptide epitope (UniCAR epitope) that is not accessible on the surface of living cells. Bifunctional adapter molecules termed target modules (TM) can cross-link UniCAR T cells with target cells. In the absence of TMs, UniCAR T cells automatically turn off. Until now, all UniCAR TMs were constructed by fusion of the UniCAR epitope to an antibody domain. To open up the wide field of low-molecular-weight compounds for retargeting of UniCAR T cells to tumor cells, and to follow in parallel the progress of UniCAR T cell therapy by PET imaging we challenged the idea to convert a PET tracer into a UniCAR-TM. For proof of concept, we selected the clinically used PET tracer PSMA-11, which binds to the prostate-specific membrane antigen overexpressed in prostate carcinoma. Here we show that fusion of the UniCAR epitope to PSMA-11 results in a low-molecular-weight theranostic compound that can be used for both retargeting of UniCAR T cells to tumor cells, and for non-invasive PET imaging and thus represents a member of a novel class of theranostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2019.1659095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791425PMC
September 2019

The Evolving Landscape of Biomarkers for Anti-PD-1 or Anti-PD-L1 Therapy.

J Clin Med 2019 Sep 25;8(10). Epub 2019 Sep 25.

National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany.

The administration of antibodies blocking the immune checkpoint molecules programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) has evolved as a very promising treatment option for cancer patients. PD-1/PD-L1 inhibition has significantly enhanced expansion, cytokine secretion, and cytotoxic activity of CD4 and CD8 T lymphocytes, resulting in enhanced antitumor responses. Anti-PD-1 or anti-PD-L1 therapy has induced tumor regression and improved clinical outcome in patients with different tumor entities, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. These findings led to the approval of various anti-PD-1 or anti-PD-L1 antibodies for the treatment of tumor patients. However, the majority of patients have failed to respond to this treatment modality. Comprehensive immune monitoring of clinical trials led to the identification of potential biomarkers distinguishing between responders and non-responders, the discovery of modes of treatment resistance, and the design of improved immunotherapeutic strategies. In this review article, we summarize the evolving landscape of biomarkers for anti-PD-1 or anti-PD-L1 therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8101534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832659PMC
September 2019

T cells engrafted with a UniCAR 28/z outperform UniCAR BB/z-transduced T cells in the face of regulatory T cell-mediated immunosuppression.

Oncoimmunology 2019;8(9):e1621676. Epub 2019 Jun 7.

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.

Adoptive transfer of chimeric antigen receptor (CAR)-equipped T cells have demonstrated astonishing clinical efficacy in hematological malignancies recently culminating in the approval of two CAR T cell products. Despite this tremendous success, CAR T cell approaches have still achieved only moderate efficacy against solid tumors. As a major obstacle, engineered conventional T cells (Tconvs) face an anti-inflammatory, hostile tumor microenvironment often infiltrated by highly suppressive regulatory T cells (Tregs). Thus, potent CAR T cell treatment of solid tumors requires efficient activation of Tconvs via their engrafted CAR to overcome Treg-mediated immunosuppression. In that regard, selecting an optimal intracellular signaling domain might represent a crucial step to achieve best clinical efficiency. To shed light on this issue and to investigate responsiveness to Treg inhibition, we engrafted Tconvs with switchable universal CARs (UniCARs) harboring intracellularly the CD3ζ domain alone or in combination with costimulatory CD28 or 4-1BB. Our studies reveal that UniCAR ζ-, and UniCAR BB/ζ-engineered Tconvs are strongly impaired by activated Tregs, whereas UniCARs providing CD28 costimulation overcome Treg-mediated suppression both and . Compared to UniCAR ζ- and UniCAR BB/ζ-modified cells, UniCAR 28/ζ-armed Tconvs secrete significantly higher amounts of Th1-related cytokines and, furthermore, levels of these cytokines are elevated even upon exposure to Tregs. Thus, in contrast to 4-1BB costimulation, CD28 signaling in UniCAR-transduced Tconvs seems to foster a pro-inflammatory milieu, which contributes to enhanced resistance to Treg suppression. Overall, our results may have significant implications for CAR T cell-based immunotherapies of solid tumors strongly invaded by Tregs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2019.1621676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685520PMC
February 2021

Current Concepts on 6-sulfo LacNAc Expressing Monocytes (slanMo).

Front Immunol 2019 22;10:948. Epub 2019 May 22.

Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany.

The human mononuclear phagocytes system consists of dendritic cells (DCs), monocytes, and macrophages having different functions in bridging innate and adaptive immunity. Among the heterogeneous population of monocytes the cell surface marker slan (6-sulfo LacNAc) identifies a specific subset of human CD14 CD16 non-classical monocytes, called slan monocytes (slanMo). In this review we discuss the identity and functions of slanMo, their contributions to immune surveillance by pro-inflammatory cytokine production, and cross talk with T cells and NK cells. We also consider the role of slanMo in the regulation of chronic inflammatory diseases and cancer. Finally, we highlight unresolved questions that should be the focus of future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.00948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540605PMC
September 2020

Impaired circulating myeloid CD1c+ dendritic cell function in human glioblastoma is restored by p38 inhibition - implications for the next generation of DC vaccines.

Oncoimmunology 2019;8(7):1593803. Epub 2019 Apr 13.

Division of Cancer and Stem Cells, Host-Tumour Interactions Group, UK.

Current treatments for glioblastoma (GBM) have limited efficacy and significant morbidity and therefore new strategies are urgently needed. Dendritic cells have the power to create anti-tumor immune responses. The greater potency of circulating dendritic cells (DC) over laboratory-generated monocyte-derived DC makes them exciting new immunotherapeutic candidates. To determine the immune status of GBM patients we initially investigated the frequency and function of circulating DC subsets. Furthermore, we tested the therapeutic potential of inhibiting the p38 mitogen-activated protein kinase pathway (p38i) in circulating DC to overcome DC dysfunction. GBM patients (n = 16) had significantly reduced numbers of the major myeloid circulating dendritic cell (cDC2) and plasmacytoid DC vs healthy controls; 1736 vs 4975 (p = 0.028) and 893 vs 2287 cells/mL (P = <0.001) respectively. This inversely correlated with dexamethasone (Dex) dose in a log-linear model, and disease status. Patients' cDC2 were immature with impaired interleukin (IL)-12 secretion, reduced IL-12:IL-10 ratio, and low HLA-DR and CD86 expression. Exposure of healthy donor cDC2 to Dex or GBM cell lysate resulted in a similar low IL-12:IL-10 ratio. Inhibition of p38 restored the IL-12:IL-10 balance in Dex or tumor lysate-conditioned healthy cDC2 and enhanced T-cell proliferation and interferon-gamma (IFNγ) production. Importantly, patient-derived cDC2 showed a similar reversal of DC dysfunction with p38i. This study demonstrates the therapeutic potential of developing the next generation of DC vaccines using enhanced p38i-conditioned cDC2. We will therefore shortly embark on a clinical trial of adoptively transferred, p38 MAPK-inhibited cDC2 in adults with GBM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2019.1593803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527277PMC
April 2019

Midostaurin abrogates CD33-directed UniCAR and CD33-CD3 bispecific antibody therapy in acute myeloid leukaemia.

Br J Haematol 2019 09 23;186(5):735-740. Epub 2019 May 23.

Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.

Combinatory therapeutic approaches of different targeted therapies in acute myeloid leukaemia are currently under preclinical/early clinical investigation. To enhance anti-tumour effects, we combined the tyrosine kinase inhibitor (TKI) midostaurin and T-cell mediated immunotherapy directed against CD33. Clinically relevant concentrations of midostaurin abrogated T-cell mediated cytotoxicity both after activation with bispecific antibodies and chimeric antigen receptor T cells. This information is of relevance for clinicians exploring T-cell mediated immunotherapy in early clinical trials. Given the profound inhibition of T-cell functionality and anti-tumour activity, we recommend specific FLT3 TKIs for further clinical testing of combinatory approaches with T-cell based immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15975DOI Listing
September 2019

Spheroid Culture of Mesenchymal Stromal Cells Results in Morphorheological Properties Appropriate for Improved Microcirculation.

Adv Sci (Weinh) 2019 Apr 19;6(8):1802104. Epub 2019 Feb 19.

Biotechnology Center Center for Molecular and Cellular Bioengineering TU Dresden Tatzberg 47-49 01307 Dresden Germany.

Human bone marrow mesenchymal stromal cells (MSCs) are used in clinical trials for the treatment of systemic inflammatory diseases due to their regenerative and immunomodulatory properties. However, intravenous administration of MSCs is hampered by cell trapping within the pulmonary capillary networks. Here, it is hypothesized that traditional 2D plastic-adherent cell expansion fails to result in appropriate morphorheological properties required for successful cell circulation. To address this issue, a method to culture MSCs in nonadherent 3D spheroids (mesenspheres) is adapted. The biological properties of mesensphere-cultured MSCs remain identical to conventional 2D cultures. However, morphorheological analyses reveal a smaller size and lower stiffness of mesensphere-derived MSCs compared to plastic-adherent MSCs, measured using real-time deformability cytometry and atomic force microscopy. These properties result in an increased ability to pass through microconstrictions in an ex vivo microcirculation assay. This ability is confirmed in vivo by comparison of cell accumulation in various organ capillary networks after intravenous injection of both types of MSCs in mouse. The findings generally identify cellular morphorheological properties as attractive targets for improving microcirculation and specifically suggest mesensphere culture as a promising approach for optimized MSC-based therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.201802104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469243PMC
April 2019

Neoadjuvant Radiochemotherapy Significantly Alters the Phenotype of Plasmacytoid Dendritic Cells and 6-Sulfo LacNAc Monocytes in Rectal Cancer.

Front Immunol 2019 29;10:602. Epub 2019 Mar 29.

Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Neoadjuvant radiochemotherapy (nRCT) can significantly influence the tumor immune architecture that plays a pivotal role in regulating tumor growth. Whereas, various studies have investigated the effect of nRCT on tumor-infiltrating T cells, little is known about its impact on the frequency and activation status of human dendritic cells (DCs). Plasmacytoid DCs (pDCs) essentially contribute to the regulation of innate and adaptive immunity and may profoundly influence tumor progression. Recent studies have revealed that higher pDC numbers are associated with poor prognosis in cancer patients. 6-sulfo LacNAc-expressing monocytes (slanMo) represent a particular proinflammatory subset of human non-classical blood monocytes that can differentiate into DCs. Recently, we have reported that activated slanMo produce various proinflammatory cytokines and efficiently stimulate natural killer cells and T lymphocytes. slanMo were also shown to accumulate in clear cell renal cell carcinoma (ccRCC) and in metastatic lymph nodes from cancer patients. Here, we investigated the influence of nRCT on the frequency of rectal cancer-infiltrating pDCs and slanMo. When evaluating rectal cancer tissues obtained from patients after nRCT, a significantly higher density of pDCs in comparison to pre-nRCT tissue samples was found. In contrast, the density of slanMo was not significantly altered by nRCT. Further studies revealed that nRCT significantly enhances the proportion of rectal cancer-infiltrating CD8 T cells expressing the cytotoxic effector molecule granzyme B. When exploring the impact of nRCT on the phenotype of rectal cancer-infiltrating pDCs and slanMo, we observed that nRCT markedly enhances the percentage of inducible nitric oxide synthase (iNOS)- or tumor necrosis factor (TNF) alpha-producing slanMo. Furthermore, nRCT significantly increased the percentage of mature CD83 pDCs in rectal cancer tissues. Moreover, the proportion of pDCs locally expressing interferon-alpha, which plays a major role in antitumor immunity, was significantly higher in post-nRCT tissues compared to pre-nRCT tumor specimens. These novel findings indicate that nRCT significantly influences the frequency and/or phenotype of pDCs, slanMo, and CD8 T cells, which may influence the clinical response of rectal cancer patients to nRCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.00602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450462PMC
August 2020

Positioning Techniques to Improve the Ultrasound Evaluation of the Elbow.

Ultrasound Q 2019 Jun;35(2):136-141

Department of Health Care Disciplines and Population Protection, Czech Technical University in Prague, Faculty of Biomedical Engineering, Kladno, Czech Republic.

We introduce an ergonomic positioning for sonographic scanning of elbow joint where the patient is lying semisupine on the examination bed. This is in contrast with the conventional positioning where the patient is sitting on the edge of the bed or across the table on a chair. Our proposed positioning is more comfortable for both the patient and ultrasound practitioner. It also allows immediate ultrasound-guided injections with lesser risk regarding a vasovagal syncope of the patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RUQ.0000000000000377DOI Listing
June 2019

Immunomodulatory effects of BRAF and MEK inhibitors: Implications for Melanoma therapy.

Pharmacol Res 2018 10 23;136:151-159. Epub 2018 Aug 23.

Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; National Centre for Tumor Diseases, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; Skin Cancer Centre at the University Cancer Center Dresden, Germany. Electronic address:

Targeted therapy with BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) provides rapid disease control with high response rates in patients with BRAF-mutant metastatic melanoma. However, the majority of patients develop resistance to therapy during the course of therapy. Immune checkpoint inhibitors show a slower onset of action with lower response rates, with responders showing sustained response. The combination of BRAFi/MEKi and immune checkpoint inhibitors combines the hope for a fast, reliable and lasting response to therapy. Preclinical data supports this hypothesis. With the help of the PubMed database, a comprehensive search and analysis of preclinical and clinical studies on the combination of BRAFi/MEKi with immune checkpoint inhibitors was performed and yielded the following results: 1) In vivo, BRAFi and MEKi have no negative effects on immune cells; BRAFi and MEKi generate 2) an immune stimulating tumor microenvironment, 3) an increased infiltration of immune cells into the tumors, 4) a better recognition of melanoma cells by immune effector cells, and 5) a better functionality of the immune effector cells. In addition, in vivo experiments 6) demonstrated a superiority of the combination treatment compared to the individual strategies in both BRAF-mutant and BRAF wild-type melanomas. In summary, available data show that both BRAFi and MEKi have beneficial effects on the antitumor immunity and the tumor microenvironment as a whole, which is mediated by different mechanisms. Currently, clinical studies are underway to investigate combinations of BRAFi and MEKi with immune checkpoint inhibitors. The results of these studies are eagerly awaited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2018.08.019DOI Listing
October 2018

Phenotype, Function, and Mobilization of 6-Sulfo LacNAc-Expressing Monocytes in Atopic Dermatitis.

Front Immunol 2018 21;9:1352. Epub 2018 Jun 21.

Department of Dermatology, Medical Faculty, University of Heidelberg, Heidelberg, Germany.

Mononuclear phagocytes (MPs) are important immune regulatory cells in atopic dermatitis (AD). We previously identified 6-sulfo LacNAc-expressing monocytes (slanMo) as TNF-α- and IL-23-producing cells in psoriatic skin lesions and as inducers of IFN-γ-, IL-17-, and IL-22-producing T cells. These cytokines are also upregulated in AD and normalize with treatment, as recently shown for dupilumab-treated patients. We here asked for the role of slanMo in AD. Increased numbers of slanMo were found in AD skin lesions. In difference to other MPs in AD, slanMo lacked expression of FcɛRI, CD1a, CD14, and CD163. slanMo from blood of patients with AD expressed increased levels of CD86 and produced IL-12 and TNF-α at higher amounts than CD14 monocytes and myeloid dendritic cells. While CD14 monocytes from patients with AD revealed a reduced IL-12 production, we observed no difference in the cytokine production comparing slanMo in AD and healthy controls. Interestingly, experimentally induced mental stress, a common trigger of flares in patients with AD, rapidly mobilized slanMo which retained their high TNF-α-producing capacity. This study identifies slanMo as a distinct population of inflammatory cells in skin lesions and as proinflammatory blood cells in patients with AD. slanMo may, therefore, represent a potent future target for treatment of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021776PMC
June 2018

From mono- to bivalent: improving theranostic properties of target modules for redirection of UniCAR T cells against EGFR-expressing tumor cells and .

Oncotarget 2018 May 22;9(39):25597-25616. Epub 2018 May 22.

UniversityCancerCenter (UCC) Dresden, Tumor Immunology, 'Carl Gustav Carus' Technische Universität Dresden, Dresden, Germany.

CAR-modified T cells show impressive results in clinical trials. However, cytokine release syndrome and "on-target, off-tumor" reactions represent most concerning side effects. To improve the safety of CAR-T cell therapy, we established a switchable CAR platform termed UniCAR system consisting of two components: UniCAR-modified T cells and tumor-specific target modules (TM). For treatment of EGFR epithelial tumors, we recently described a monovalent nanobody-based α-EGFR TM, either expressed in bacteria or eukaryotic cells. In spite of the identical primary sequence the eukaryotic TM showed a reduced killing capability and affinity. Here we describe a novel bivalent α-EGFR-EGFR TM. As expected, the avidity of the bivalent TM is higher than that of its monovalent counterpart. Binding of neither the monovalent α-EGFR TM nor the bivalent α-EGFR-EGFR TM to EGFR effected the EGF-mediated signaling. While the monovalent α-EGFR TM could only mediate the killing of tumor cells expressing high levels of EGFR, the bivalent α-EGFR-EGFR TM could redirect UniCAR T cells to tumor cells expressing low levels of EGFR. According to PET experiments , the increased avidity of the bivalent α-EGFR-EGFR TM improves the enrichment at the tumor site and its use for PET imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986651PMC
May 2018