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  1. Article ; Online: Twin study dissects CXCR3

    Ingelfinger, Florian / Kuiper, Kirsten L / Ulutekin, Can / Rindlisbacher, Lukas / Mundt, Sarah / Gerdes, Lisa Ann / Smolders, Joost / van Luijn, Marvin M / Becher, Burkhard

    Med (New York, N.Y.)

    2024  Volume 5, Issue 4, Page(s) 368–373.e3

    Abstract: Background: In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to ...

    Abstract Background: In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets.
    Methods: In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals.
    Findings: The frequencies of CXCR3
    Conclusions: Circulating CXCR3
    Funding: This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no. 882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).
    MeSH term(s) Humans ; Multiple Sclerosis/genetics ; Memory B Cells ; Epstein-Barr Virus Infections ; Herpesvirus 4, Human ; Natalizumab ; Receptors, CXCR3
    Chemical Substances Natalizumab ; CXCR3 protein, human ; Receptors, CXCR3
    Language English
    Publishing date 2024-03-25
    Publishing country United States
    Document type Twin Study ; Journal Article
    ISSN 2666-6340
    ISSN (online) 2666-6340
    DOI 10.1016/j.medj.2024.02.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: IL-23 stabilizes an effector T

    Wertheimer, Tobias / Zwicky, Pascale / Rindlisbacher, Lukas / Sparano, Colin / Vermeer, Marijne / de Melo, Bruno Marcel Silva / Haftmann, Claudia / Rückert, Tamina / Sethi, Aakriti / Schärli, Stefanie / Huber, Anna / Ingelfinger, Florian / Xu, Caroline / Kim, Daehong / Häne, Philipp / Fonseca da Silva, André / Muschaweckh, Andreas / Nunez, Nicolas / Krishnarajah, Sinduya /
    Köhler, Natalie / Zeiser, Robert / Oukka, Mohamed / Korn, Thomas / Tugues, Sonia / Becher, Burkhard

    Nature immunology

    2024  Volume 25, Issue 3, Page(s) 512–524

    Abstract: Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we ... ...

    Abstract Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. Among IL-23-sensing cells, we identified a subset of tumor-infiltrating regulatory T (T
    MeSH term(s) Animals ; Humans ; Mice ; Cytokines ; Interleukin-23/genetics ; Neoplasms/genetics ; T-Lymphocytes ; Tumor Microenvironment
    Chemical Substances Cytokines ; Interleukin-23
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/s41590-024-01755-7
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    Zs.A 5294: Show issues Location:
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  3. Article ; Online: Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell-dependent regression of glioblastoma.

    Look, Thomas / Puca, Emanuele / Bühler, Marcel / Kirschenbaum, Daniel / De Luca, Roberto / Stucchi, Riccardo / Ravazza, Domenico / Di Nitto, Cesare / Roth, Patrick / Katzenelenbogen, Yonatan / Weiner, Assaf / Rindlisbacher, Lukas / Becher, Burkhard / Amit, Ido / Weller, Michael / Neri, Dario / Hemmerle, Teresa / Weiss, Tobias

    Science translational medicine

    2023  Volume 15, Issue 697, Page(s) eadf2281

    Abstract: Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here, we investigated combination therapies based on L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively ... ...

    Abstract Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here, we investigated combination therapies based on L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes to cancer neovasculature. Using immunocompetent orthotopic glioma mouse models, we identified strong anti-glioma activity of L19TNF in combination with the alkylating agent CCNU, which cured the majority of tumor-bearing mice, whereas monotherapies only had limited efficacy. In situ and ex vivo immunophenotypic and molecular profiling in the mouse models revealed that L19TNF and CCNU induced tumor DNA damage and treatment-associated tumor necrosis. In addition, this combination also up-regulated tumor endothelial cell adhesion molecules, promoted the infiltration of immune cells into the tumor, induced immunostimulatory pathways, and decreased immunosuppression pathways. MHC immunopeptidomics demonstrated that L19TNF and CCNU increased antigen presentation on MHC class I molecules. The antitumor activity was T cell dependent and completely abrogated in immunodeficient mouse models. On the basis of these encouraging results, we translated this treatment combination to patients with glioblastoma. The clinical translation is ongoing but already shows objective responses in three of five patients in the first recurrent glioblastoma patient cohort treated with L19TNF in combination with CCNU (NCT04573192).
    MeSH term(s) Animals ; Mice ; Glioblastoma/drug therapy ; T-Lymphocytes ; Neoplasm Recurrence, Local ; Tumor Necrosis Factor-alpha ; Disease Models, Animal ; Lomustine
    Chemical Substances Tumor Necrosis Factor-alpha ; Lomustine (7BRF0Z81KG)
    Language English
    Publishing date 2023-05-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.adf2281
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    Zs.A 6941: Show issues Location:
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  4. Article ; Online: Azathioprine therapy induces selective NK cell depletion and IFN-γ deficiency predisposing to herpesvirus reactivation.

    Ingelfinger, Florian / Sparano, Colin / Bamert, David / Reyes-Leiva, David / Sethi, Aakriti / Rindlisbacher, Lukas / Zwicky, Pascale / Kreutmair, Stefanie / Widmer, Corinne C / Mundt, Sarah / Cortés-Vicente, Elena / Tugues, Sonia / Becher, Burkhard / Schreiner, Bettina

    The Journal of allergy and clinical immunology

    2022  Volume 151, Issue 1, Page(s) 280–286.e2

    Abstract: Background: Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and ...

    Abstract Background: Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and reducing the numbers of circulating B and T lymphocytes. Case reports indicate increased risk for serious infections that can occur despite regular measurements of lymphocyte counts during azathioprine therapy.
    Objective: We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use.
    Methods: Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients.
    Results: Azathioprine therapy selectively induced pronounced CD56
    Conclusion: Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice.
    MeSH term(s) Humans ; Azathioprine/adverse effects ; Killer Cells, Natural ; Interferon-gamma/pharmacology ; Herpesviridae ; Myasthenia Gravis/drug therapy ; Myasthenia Gravis/chemically induced
    Chemical Substances Azathioprine (MRK240IY2L) ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2022-09-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 121011-7
    ISSN 1097-6825 ; 1085-8725 ; 0091-6749
    ISSN (online) 1097-6825 ; 1085-8725
    ISSN 0091-6749
    DOI 10.1016/j.jaci.2022.09.010
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  5. Article ; Online: NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis.

    Marinović, Sonja / Lenartić, Maja / Mladenić, Karlo / Šestan, Marko / Kavazović, Inga / Benić, Ante / Krapić, Mia / Rindlisbacher, Lukas / Cokarić Brdovčak, Maja / Sparano, Colin / Litscher, Gioana / Turk Wensveen, Tamara / Mikolašević, Ivana / Fučkar Čupić, Dora / Bilić-Zulle, Lidija / Steinle, Aleksander / Waisman, Ari / Hayday, Adrian / Tugues, Sonia /
    Becher, Burkhard / Polić, Bojan / Wensveen, Felix M

    Science immunology

    2023  Volume 8, Issue 87, Page(s) eadd1599

    Abstract: Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can ... ...

    Abstract Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A
    MeSH term(s) Animals ; Humans ; Mice ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Inflammation/pathology ; Interleukin-17/metabolism ; Liver Cirrhosis/metabolism ; NK Cell Lectin-Like Receptor Subfamily K ; Non-alcoholic Fatty Liver Disease ; T-Lymphocytes/metabolism
    Chemical Substances Interleukin-17 ; NK Cell Lectin-Like Receptor Subfamily K ; Klrk1 protein, mouse
    Language English
    Publishing date 2023-09-29
    Publishing country United States
    Document type Journal Article
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.add1599
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  6. Article ; Online: MDM2 Inhibition Enhances Immune Checkpoint Inhibitor Efficacy by Increasing IL15 and MHC Class II Production.

    Langenbach, Marlene / Giesler, Sophie / Richtsfeld, Stefan / Costa-Pereira, Sara / Rindlisbacher, Lukas / Wertheimer, Tobias / Braun, Lukas M / Andrieux, Geoffroy / Duquesne, Sandra / Pfeifer, Dietmar / Woessner, Nadine M / Menssen, Hans D / Taromi, Sanaz / Duyster, Justus / Börries, Melanie / Brummer, Tilman / Blazar, Bruce R / Minguet, Susana / Turko, Patrick /
    Levesque, Mitchell P / Becher, Burkhard / Zeiser, Robert

    Molecular cancer research : MCR

    2023  Volume 21, Issue 8, Page(s) 849–864

    Abstract: The treatment of patients with metastatic melanoma with immune checkpoint inhibitors (ICI) leads to impressive response rates but primary and secondary resistance to ICI reduces progression-free survival. Novel strategies that interfere with resistance ... ...

    Abstract The treatment of patients with metastatic melanoma with immune checkpoint inhibitors (ICI) leads to impressive response rates but primary and secondary resistance to ICI reduces progression-free survival. Novel strategies that interfere with resistance mechanisms are key to further improve patient outcome during ICI therapy. P53 is often inactivated by mouse-double-minute-2 (MDM2), which may decrease immunogenicity of melanoma cells. We analyzed primary patient-derived melanoma cell lines, performed bulk sequencing analysis of patient-derived melanoma samples, and used melanoma mouse models to investigate the role of MDM2-inhibition for enhanced ICI therapy. We found increased expression of IL15 and MHC-II in murine melanoma cells upon p53 induction by MDM2-inhibition. MDM2-inhibitor induced MHC-II and IL15-production, which was p53 dependent as Tp53 knockdown blocked the effect. Lack of IL15-receptor in hematopoietic cells or IL15 neutralization reduced the MDM2-inhibition/p53-induction-mediated antitumor immunity. P53 induction by MDM2-inhibition caused anti-melanoma immune memory as T cells isolated from MDM2-inhibitor-treated melanoma-bearing mice exhibited anti-melanoma activity in secondary melanoma-bearing mice. In patient-derived melanoma cells p53 induction by MDM2-inhibition increased IL15 and MHC-II. IL15 and CIITA expressions were associated with a more favorable prognosis in patients bearing WT but not TP53-mutated melanoma.
    Implications: MDM2-inhibition represents a novel strategy to enhance IL15 and MHC-II-production, which disrupts the immunosuppressive tumor microenvironment. On the basis of our findings, a clinical trial combining MDM2-inhibition with anti-PD-1 immunotherapy for metastatic melanoma is planned.
    MeSH term(s) Animals ; Mice ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Interleukin-15/metabolism ; Interleukin-15/therapeutic use ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Cell Line, Tumor ; Melanoma/drug therapy ; Melanoma/genetics ; Antineoplastic Agents/pharmacology ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Microenvironment
    Chemical Substances Tumor Suppressor Protein p53 ; Interleukin-15 ; Immune Checkpoint Inhibitors ; Antineoplastic Agents ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
    Language English
    Publishing date 2023-06-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2098788-2
    ISSN 1557-3125 ; 1541-7786
    ISSN (online) 1557-3125
    ISSN 1541-7786
    DOI 10.1158/1541-7786.MCR-22-0898
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    Zs.A 5744: Show issues Location:
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  7. Article ; Online: Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma.

    Agliardi, Giulia / Liuzzi, Anna Rita / Hotblack, Alastair / De Feo, Donatella / Núñez, Nicolás / Stowe, Cassandra L / Friebel, Ekaterina / Nannini, Francesco / Rindlisbacher, Lukas / Roberts, Thomas A / Ramasawmy, Rajiv / Williams, Iwan P / Siow, Bernard M / Lythgoe, Mark F / Kalber, Tammy L / Quezada, Sergio A / Pule, Martin A / Tugues, Sonia / Straathof, Karin /
    Becher, Burkhard

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 444

    Abstract: Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is ... ...

    Abstract Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4
    MeSH term(s) Animals ; Brain/diagnostic imaging ; Brain/immunology ; Brain/pathology ; Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/immunology ; Brain Neoplasms/pathology ; Brain Neoplasms/therapy ; Cell Line, Tumor/transplantation ; Disease Models, Animal ; ErbB Receptors/immunology ; Female ; Glioblastoma/diagnostic imaging ; Glioblastoma/immunology ; Glioblastoma/pathology ; Glioblastoma/therapy ; Humans ; Immunoconjugates/administration & dosage ; Immunoconjugates/immunology ; Immunoglobulin Fc Fragments/administration & dosage ; Immunoglobulin Fc Fragments/immunology ; Immunotherapy, Adoptive/methods ; Injections, Intralesional/methods ; Interleukin-12/administration & dosage ; Interleukin-12/immunology ; Magnetic Resonance Imaging, Interventional ; Mice ; Receptors, Chimeric Antigen/immunology ; Single-Chain Antibodies/administration & dosage ; Single-Chain Antibodies/immunology ; T-Lymphocytes, Regulatory/immunology ; Tumor Microenvironment/immunology
    Chemical Substances Immunoconjugates ; Immunoglobulin Fc Fragments ; Receptors, Chimeric Antigen ; Single-Chain Antibodies ; epidermal growth factor receptor VIII ; Interleukin-12 (187348-17-0) ; ErbB Receptors (EC 2.7.10.1)
    Language English
    Publishing date 2021-01-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-20599-x
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