@article{MunawarZhouPrommersbergeretal.2023,
  author    = {Munawar, Umair and Zhou, Xiang and Prommersberger, Sabrina and Nerreter, Silvia and Vogt, Cornelia and Steinhardt, Maximilian J. and Truger, Marietta and Mersi, Julia and Teufel, Eva and Han, Seungbin and Haertle, Larissa and Banholzer, Nicole and Eiring, Patrick and Danhof, Sophia and Navarro-Aguadero, Miguel Angel and Fernandez-Martin, Adrian and Ortiz-Ruiz, Alejandra and Barrio, Santiago and Gallardo, Miguel and Valeri, Antonio and Castellano, Eva and Raab, Peter and Rudert, Maximilian and Haferlach, Claudia and Sauer, Markus and Hudecek, Michael and Martinez-Lopez, J. and Waldschmidt, Johannes and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, K. Martin},
  title     = {Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma},
  series = {Communications Biology},
  volume    = {6},
  journal   = {Communications Biology},
  doi       = {10.1038/s42003-023-05683-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357609},
  year      = {2023},
  abstract  = {The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.},
  language  = {en}
}
@article{StaudtZieglerMartinVisekrunaetal.2023,
  author    = {Staudt, Sarah and Ziegler-Martin, Kai and Visekruna, Alexander and Slingerland, John and Shouval, Roni and Hudecek, Michael and Van den Brink, Marcel and Luu, Maik},
  title     = {Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1269015},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-328019},
  year      = {2023},
  abstract  = {The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy.},
  language  = {en}
}
@article{LauruschkatMuchsinReinetal.2023,
  author    = {Lauruschkat, Chris David and Muchsin, Ihsan and Rein, Alice and Erhard, Florian and Grathwohl, Denise and D{\"o}lken, Lars and K{\"o}chel, Carolin and Falk, Christine Susanne and Einsele, Hermann and Wurster, Sebastian and Grigoleit, G{\"o}tz Ulrich and Kraus, Sabrina},
  title     = {CD4+ T cells are the major predictor of HCMV control in allogeneic stem cell transplant recipients on letermovir prophylaxis},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1148841},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316982},
  year      = {2023},
  abstract  = {Introduction Human cytomegalovirus (HCMV) causes significant morbidity and mortality in allogeneic stem cell transplant (alloSCT) recipients. Recently, antiviral letermovir prophylaxis during the first 100 days after alloSCT replaced PCR-guided preemptive therapy as the primary standard of care for HCMV reactivations. Here, we compared NK-cell and T-cell reconstitution in alloSCT recipients receiving preemptive therapy or letermovir prophylaxis in order to identify potential biomarkers predicting prolonged and symptomatic HCMV reactivation. Methods To that end, the NK-cell and T-cell repertoire of alloSCT recipients managed with preemptive therapy (n=32) or letermovir prophylaxis (n=24) was characterized by flow cytometry on days +30, +60, +90 and +120 after alloSCT. Additionally, background-corrected HCMV-specific T-helper (CD4+IFNγ+) and cytotoxic (CD8+IFNγ+CD107a+) T cells were quantified after pp65 stimulation. Results Compared to preemptive therapy, letermovir prophylaxis prevented HCMV reactivation and decreased HCMV peak viral loads until days +120 and +365. Letermovir prophylaxis resulted in decreased T-cell numbers but increased NK-cell numbers. Interestingly, despite the inhibition of HCMV, we found high numbers of "memory-like" (CD56dimFcεRIγ- and/or CD159c+) NK cells and an expansion of HCMV-specific CD4+ and CD8+ T cells in letermovir recipients. We further compared immunological readouts in patients on letermovir prophylaxis with non/short-term HCMV reactivation (NSTR) and prolonged/symptomatic HCMV reactivation (long-term HCMV reactivation, LTR). Median HCMV-specific CD4+ T-cell frequencies were significantly higher in NSTR patients (day +60, 0.35 \% vs. 0.00 \% CD4+IFNγ+/CD4+ cells, p=0.018) than in patients with LTR, whereas patients with LTR had significantly higher median regulatory T-cell (Treg) frequencies (day +90, 2.2 \% vs. 6.2 \% CD4+CD25+CD127dim/CD4+ cells, p=0.019). ROC analysis confirmed low HCMV specific CD4+ (AUC on day +60: 0.813, p=0.019) and high Treg frequencies (AUC on day +90: 0.847, p=0.021) as significant predictors of prolonged and symptomatic HCMV reactivation. Discussion Taken together, letermovir prophylaxis delays HCMV reactivation and alters NK- and T-cell reconstitution. High numbers of HCMV-specific CD4+ T cells and low numbers of Tregs seem to be pivotal to suppress post-alloSCT HCMV reactivation during letermovir prophylaxis. Administration of more advanced immunoassays that include Treg signature cytokines might contribute to the identification of patients at high-risk for long-term and symptomatic HCMV reactivation who might benefit from prolonged administration of letermovir.},
  language  = {en}
}
@article{ElgheznawyOefteringEnglertetal.2023,
  author    = {Elgheznawy, Amro and {\"O}ftering, Patricia and Englert, Maximilian and Mott, Kristina and Kaiser, Friederike and Kusch, Charly and Gbureck, Uwe and B{\"o}sl, Michael R. and Schulze, Harald and Nieswandt, Bernhard and V{\"o}gtle, Timo and Hermanns, Heike M.},
  title     = {Loss of zinc transporters ZIP1 and ZIP3 augments platelet reactivity in response to thrombin and accelerates thrombus formation in vivo},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1197894},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320154},
  year      = {2023},
  abstract  = {Zinc (Zn2+) is considered as important mediator of immune cell function, thrombosis and haemostasis. However, our understanding of the transport mechanisms that regulate Zn2+ homeostasis in platelets is limited. Zn2+ transporters, ZIPs and ZnTs, are widely expressed in eukaryotic cells. Using mice globally lacking ZIP1 and ZIP3 (ZIP1/3 DKO), our aim was to explore the potential role of these Zn2+ transporters in maintaining platelet Zn2+ homeostasis and in the regulation of platelet function. While ICP-MS measurements indicated unaltered overall Zn2+ concentrations in platelets of ZIP1/3 DKO mice, we observed a significantly increased content of FluoZin3-stainable free Zn2+, which, however, appears to be released less efficiently upon thrombin-stimulated platelet activation. On the functional level, ZIP1/3 DKO platelets exhibited a hyperactive response towards threshold concentrations of G protein-coupled receptor (GPCR) agonists, while immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor agonist signalling was unaffected. This resulted in enhanced platelet aggregation towards thrombin, bigger thrombus volume under flow ex vivo and faster in vivo thrombus formation in ZIP1/3 DKO mice. Molecularly, augmented GPCR responses were accompanied by enhanced Ca2+ and PKC, CamKII and ERK1/2 signalling. The current study thereby identifies ZIP1 and ZIP3 as important regulators for the maintenance of platelet Zn2+ homeostasis and function.},
  language  = {en}
}
@article{ZaitsevaAnanyWajantetal.2023,
  author    = {Zaitseva, Olena and Anany, Mohamed and Wajant, Harald and Lang, Isabell},
  title     = {Basic characterization of antibodies targeting receptors of the tumor necrosis factor receptor superfamily},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1115667},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311407},
  year      = {2023},
  abstract  = {Many new immunotherapeutic approaches aim on the stimulatory targeting of receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) using antibodies with intrinsic or conditional agonism. There is an initial need to characterize corresponding TNFRSF receptor (TNFR)-targeting antibodies with respect to affinity, ligand binding, receptor activation and the epitope recognized. Here, we report a collection of simple and matched protocols enabling the detailed investigation of these aspects by help of Gaussia princeps luciferase (GpL) fusion proteins and analysis of interleukin-8 (IL8) production as an easily measurable readout of TNFR activation. In a first step, the antibodies and antibody variants of interest are transiently expressed in human embryonal kidney 293 cells, either in non-modified form or as fusion proteins with GpL as a reporter domain. The supernatants containing the antibody-GpL fusion proteins can then be used without further purification in cell-free and/or cellular binding studies to determine affinity. Similarly, binding studies with mutated TNFR variants enable the characterization of the antibody binding site within the TNFR ectodomain. Furthermore, in cellular binding studies with GpL fusion proteins of soluble TNFL molecules, the ability of the non-modified antibody variants to interfere with TNFL-TNFR interaction can be analyzed. Last but not least, we describe a protocol to determine the intrinsic and the Fc gamma receptor (FcγR)-dependent agonism of anti-TNFR antibodies which exploits i) the capability of TNFRs to trigger IL8 production in tumor cell lines lacking expression of FcγRs and ii) vector- and FcγR-transfected cells, which produce no or only very low amounts of human IL8. The presented protocols only require standard molecular biological equipment, eukaryotic cell culture and plate readers for the quantification of luminescent and colorimetric signals.},
  language  = {en}
}
@article{GrunzKunzBaumannetal.2023,
  author    = {Grunz, Jan-Peter and Kunz, Andreas Steven and Baumann, Freerk T. and Hasenclever, Dirk and Sieren, Malte Maria and Heldmann, Stefan and Bley, Thorsten Alexander and Einsele, Hermann and Knop, Stefan and Jundt, Franziska},
  title     = {Assessing osteolytic lesion size on sequential CT scans is a reliable study endpoint for bone remineralization in newly diagnosed multiple myeloma},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {15},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15154008},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362526},
  year      = {2023},
  abstract  = {Multiple myeloma (MM) frequently induces persisting osteolytic manifestations despite hematologic treatment response. This study aimed to establish a biometrically valid study endpoint for bone remineralization through quantitative and qualitative analyses in sequential CT scans. Twenty patients (seven women, 58 ± 8 years) with newly diagnosed MM received standardized induction therapy comprising the anti-SLAMF7 antibody elotuzumab, carfilzomib, lenalidomide, and dexamethasone (E-KRd). All patients underwent whole-body low-dose CT scans before and after six cycles of E-KRd. Two radiologists independently recorded osteolytic lesion sizes, as well as the presence of cortical destruction, pathologic fractures, rim and trabecular sclerosis. Bland-Altman analyses and Krippendorff's α were employed to assess inter-reader reliability, which was high for lesion size measurement (standard error 1.2 mm) and all qualitative criteria assessed (α ≥ 0.74). After six cycles of E-KRd induction, osteolytic lesion size decreased by 22\% (p \< 0.001). While lesion size response did not correlate with the initial lesion size at baseline imaging (Pearson's r = 0.144), logistic regression analysis revealed that the majority of responding osteolyses exhibited trabecular sclerosis (p \< 0.001). The sum of osteolytic lesion sizes on sequential CT scans defines a reliable study endpoint to characterize bone remineralization. Patient level response is strongly associated with the presence of trabecular sclerosis.},
  language  = {en}
}
@phdthesis{Muhr2023,
  author    = {Muhr, Christiane},
  title     = {Optimierung eines molekularen Verfahrens zur Quantifizierung des Chim{\"a}rismus nach allogener Stammzelltransplantation},
  doi       = {10.25972/OPUS-32127},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321277},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Die molekulare Chim{\"a}rismusdiagnostik stellt einen essenziellen Teil der Therapie{\"u}berwachung nach allogener HSZT dar. In der Uniklinik W{\"u}rzburg wird hierbei mittels qPCR eines Panels von 21 Allelen eine Informativit{\"a}t von 95 \% und eine Sensitivit{\"a}t von 0,1-0,01 \% erreicht. Ziel der Arbeit war eine Optimierung dieser in unserem Labor angewandten Methode zur Chim{\"a}rismusanalyse in puncto Sensitivit{\"a}t und Informativit{\"a}t. Es wurde untersucht, ob durch Steigerung des DNA-Inputs in die qPCR eine Sensitivit{\"a}tserh{\"o}hung erzielt werden kann, ohne dass PCR-Inhibition auftritt. Dabei erwies sich ein DNA-Input von 250 ng als ideal f{\"u}r eine verl{\"a}sslichere Detektion von 0,01 \% Empf{\"a}ngerzellen. PCR-Inhibition trat nicht auf. Zur Deckung des damit einhergehendem erh{\"o}hten DNA-Bedarf wurden verschiedene Elutionsmethoden der DNA-Extraktion verglichen, wobei durch Extraktion mit dem QIAamp DNA Blood Midi-Kit und Elution mit 2 x 200 μl AE-Puffer der h{\"o}chste DNA-Ertrag gewonnen wurde. Zur Erh{\"o}hung der Informativit{\"a}t wurde die Anwendbarkeit eines Primersets f{\"u}r qPCR des SNP rs713753 evaluiert. Hierbei zeigte sich eine m{\"a}ßige Eignung: Beide Allele des SNP gemeinsam ergaben eine gute Informativit{\"a}t f{\"u}r Empf{\"a}ngerdiskriminierung von 37,5 \%. Die qPCR-Effizienzen der lokusspezifischen Referenz und des Allels C waren nahezu optimal, die des Allels T lag lediglich bei 0,87. Die Sensitivit{\"a}t der spezifischen Allele lag bei max. 0,1 \%. Sofern auch hier eine Sensitivit{\"a}tssteigerung durch Erh{\"o}hung des DNA-Inputs in die qPCR ohne Auftreten unspezifischer Amplifikation m{\"o}glich ist, w{\"a}re eine Integration der qPCR des SNP rs713753 in die Routinediagnostik denkbar. Zusammenfassend ist eine Optimierung der in unserem Labor angewandten Methode zur Chim{\"a}rismusdiagnostik hinsichtlich Sensitivit{\"a}t und Informativit{\"a}t durchaus m{\"o}glich. Eine Erh{\"o}hung des DNA-Inputs ist dabei am simpelsten umsetzbar; zur Etablierung weiterer Allele bedarf es zus{\"a}tzlicher Experimente.},
  subject      = {Real time quantitative PCR},
  language  = {de}
}
@article{SolimandoBittrichShahinietal.2023,
  author    = {Solimando, Antonio G. and Bittrich, Max and Shahini, Endrit and Albanese, Federica and Fritz, Georg and Krebs, Markus},
  title     = {Determinants of COVID-19 disease severity - lessons from primary and secondary immune disorders including cancer},
  series = {International Journal of Molecular Sciences},
  volume    = {24},
  journal   = {International Journal of Molecular Sciences},
  number    = {10},
  issn      = {1422-0067},
  doi       = {10.3390/ijms24108746},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319412},
  year      = {2023},
  abstract  = {At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders — including patients suffering from cancer — were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients' risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients.},
  language  = {en}
}
@article{LuuSchuetzLauthetal.2023,
  author    = {Luu, Maik and Sch{\"u}tz, Burkhard and Lauth, Matthias and Visekruna, Alexander},
  title     = {The impact of gut microbiota-derived metabolites on the tumor immune microenvironment},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {5},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15051588},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311005},
  year      = {2023},
  abstract  = {Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way.},
  language  = {en}
}
@article{NicklEckGoedertetal.2023,
  author    = {Nickl, Vera and Eck, Juliana and Goedert, Nicolas and H{\"u}bner, Julian and Nerreter, Thomas and Hagemann, Carsten and Ernestus, Ralf-Ingo and Schulz, Tim and Nickl, Robert Carl and Keßler, Almuth Friederike and L{\"o}hr, Mario and Rosenwald, Andreas and Breun, Maria and Monoranu, Camelia Maria},
  title     = {Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {10},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15102698},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319249},
  year      = {2023},
  abstract  = {While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future.},
  language  = {en}
}