Publications by authors named "Julius C Fischer"

14 Publications

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Evaluation of practical experiences of German speaking radiation oncologists in combining radiation therapy with checkpoint blockade.

Sci Rep 2021 04 7;11(1):7624. Epub 2021 Apr 7.

Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany.

The results of this survey reveal current clinical practice in the handling of combined radioimmunotherapy with Immune Checkpoint Inhibitors (RT + ICI). We aim to provide a basis to open a discussion for clinical application of RT + ICI by analyzation of experts' assessment. We conducted a survey with 24 items with a focus on side effects of RT + ICI, common practice of scheduling and handling of adverse events. After pilot testing by radiation oncology experts the link to the online survey was sent to all members of the German Society of Radiation Oncology (DEGRO). In total, 51 radiation oncologists completed the questionnaire. Pulmonary toxicity under RT + ICI with ICIs was reported most frequently. Consensus was observed for bone and soft tissue RT of the limbs in favor for no interruption of ICIs. For cranial RT half of the participants do not suspend ICIs during normofractionated radiotherapy (nfRT) or stereotactic hypofractionated RT (SRT). More participants pause ICIs for central than for peripheral thoracic region. Maintenance therapy with ICIs is mostly not interrupted prior to RT. For management of RT associated pneumonitis under durvalumab the majority of 86.3% suggest corticosteroid therapy and 76.5% would postpone the next cycle of ICI therapy. The here obtained assessment and experiences by radiation oncologists reveal a large variability in practical handling of combined RT + ICI. Until scientific evidence is available a discussion for current clinical application of RT + ICI should be triggered. Interdisciplinary consensus guidelines with practical recommendations are required.
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http://dx.doi.org/10.1038/s41598-021-86863-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027172PMC
April 2021

Type I interferon signaling before hematopoietic stem cell transplantation lowers donor T cell activation via reduced allogenicity of recipient cells.

Sci Rep 2019 10 18;9(1):14955. Epub 2019 Oct 18.

Department of Medicine III, Technical University of Munich (TUM), School of Medicine, Klinikum rechts der Isar TUM, Ismaninger Straße 22, 81675, Munich, Germany.

Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterized. We applied RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Using IFN-I receptor-deficient donor T cells and hematopoietic cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted allogeneic T-cells. The reduced allogenicity of CD11c recipient cells was dependent on IFN-I signaling. Notably, this immunosuppressive function of DCs was restricted to a scenario where tissue damage occurs. Our findings uncover a context (damage by TBI) and IFN-I dependent modulation of T cells by DCs and extend the understanding about the cellular targets of IFN-I during allo-HSCT and GVHD.
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http://dx.doi.org/10.1038/s41598-019-51431-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800427PMC
October 2019

RIG-I activation is critical for responsiveness to checkpoint blockade.

Sci Immunol 2019 09;4(39)

Department of Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.

Achieving durable clinical responses to immune checkpoint inhibitors remains a challenge. Here, we demonstrate that immunotherapy with anti-CTLA-4 and its combination with anti-PD-1 rely on tumor cell-intrinsic activation of the cytosolic RNA receptor RIG-I. Mechanistically, tumor cell-intrinsic RIG-I signaling induced caspase-3-mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103 dendritic cells, subsequent expansion of tumor antigen-specific CD8 T cells, and their accumulation within the tumor tissue. Consistently, therapeutic targeting of RIG-I with 5'- triphosphorylated RNA in both tumor and nonmalignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade in several preclinical cancer models. In humans, transcriptome analysis of primary melanoma samples revealed a strong association between high expression of (the gene encoding RIG-I), T cell receptor and antigen presentation pathway activity, and prolonged overall survival. Moreover, in patients with melanoma treated with anti-CTLA-4 checkpoint blockade, high RIG-I transcriptional activity significantly associated with durable clinical responses. Our data thus identify activation of RIG-I signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor-mediated immunotherapy of cancer.
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http://dx.doi.org/10.1126/sciimmunol.aau8943DOI Listing
September 2019

Targeting intrinsic RIG-I signaling turns melanoma cells into type I interferon-releasing cellular antitumor vaccines.

Oncoimmunology 2019;8(4):e1570779. Epub 2019 Feb 11.

Medizinische Klinik und Poliklinik 3, Klinikum rechts der Isar, Technische Universität, Munich, Germany.

Resistance to cell death and evasion of immunosurveillance are major causes of cancer persistence and progression. Tumor cell-intrinsic activation of the RNA receptor retinoic acid-inducible gene-I (RIG-I) can trigger an immunogenic form of programmed tumor cell death, but its impact on antitumor responses remains largely unexplored. We show that activation of intrinsic RIG-I signaling induces melanoma cell death that enforces cross-presentation of tumor-associated antigens by bystander dendritic cells. This results in systemic expansion and activation of tumor-antigen specific T cells with subsequent regression of pre-established melanoma. These processes were dependent on the signaling hub MAVS and type I interferon (IFN-I) signaling in the host cell. Using melanoma cells deficient for the transcription factors IRF3 and IRF7, we demonstrate that RIG-I-activated tumor cells used as a vaccine are a relevant source of IFN-I during T cell cross-priming . Thus, our findings may facilitate translational development of personalized anticancer vaccines.
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http://dx.doi.org/10.1080/2162402X.2019.1570779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422402PMC
February 2019

RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade.

EBioMedicine 2019 Mar 6;41:146-155. Epub 2019 Mar 6.

Medizinische Klinik und Poliklinik III, Klinikum rechts der Isar, Technische Universität, Munich, Germany. Electronic address:

Background: Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches.

Methods: Here we established a vaccination strategy that combines engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4 blockade. We used in vitro transcribed 5'-triphosphorylated RNA (3pRNA) to therapeutically target the RIG-I pathway. We performed in vitro functional analysis in bone-marrow derived dendritic cells and investigated RIG-I-enhanced vaccines in different murine melanoma models.

Findings: We found that protein vaccination together with RIG-I ligation via 3pRNA strongly synergizes with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8 T cells that translates into potent antitumor immunity. RIG-I-induced cross-priming of cytotoxic T cells as well as antitumor immunity were dependent on the host adapter protein MAVS and type I interferon (IFN-I) signaling and were mediated by dendritic cells.

Interpretation: Overall, our data demonstrate the potency of a novel combinatorial vaccination strategy combining RIG-I-driven immunization with CTLA-4 blockade to prevent and treat experimental melanoma. FUND: German Research Foundation (SFB 1335, SFB 1371), EMBO, Else Kröner-Fresenius-Foundation, German Cancer Aid, European Hematology Association, DKMS Foundation for Giving Life, Dres. Carl Maximilian and Carl Manfred Bayer-Foundation.
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http://dx.doi.org/10.1016/j.ebiom.2019.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444128PMC
March 2019

XIAP deficiency in hematopoietic recipient cells drives donor T-cell activation and GvHD in mice.

Eur J Immunol 2019 03 3;49(3):504-507. Epub 2019 Jan 3.

Medizinische Klinik III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Patients with X-linked lymphoproliferative syndrome type 2 (XLP-2) (BIRC4 deficiency) suffer from hyperinflammation often observed during the conditioning regimen prior to allogeneic bone marrow transplant. This article shows that in mice hematopoietic recipient cells contribute to graft-versus-host disease by the secretion of elevated levels of proinflammatory cytokines during engraftment when BIRC4 is absent.
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http://dx.doi.org/10.1002/eji.201847818DOI Listing
March 2019

Regeneration After Radiation- and Immune-Mediated Tissue Injury Is Not Enhanced by Type III Interferon Signaling.

Int J Radiat Oncol Biol Phys 2019 03 29;103(4):970-976. Epub 2018 Nov 29.

Klinik und Poliklinik für Innere Medizin 3, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Purpose: Type I interferon (IFN-I) and interleukin (IL)-22 modulate regeneration of the thymus and intestinal epithelial cells (IECs) after cytotoxic stress such as irradiation. Radiation-induced damage to thymic tissues and IECs is a crucial aspect during the pathogenesis of inadequate immune reconstitution and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative total body irradiation (TBI), respectively. IL-22 and IFN-I reduce the severity of acute GVHD after allo-HSCT with myeloablative TBI. However, the role of biologically related type III interferon (IFN-III), also known as interferon lambda (IFN-λ) or IL-28, in this context is unclear. We therefore studied the role of the IFN-III pathway in thymic regeneration and GVHD after TBI and allo-HSCT.

Methods And Materials: Cohoused wild-type (WT) and IFN-III receptor-deficient (IL-28 receptor alpha subunit-deficient/IL-28Ra) mice were analyzed in models of TBI-induced thymus damage and a model of GVHD after allo-HSCT with myeloablative TBI. PASylated IFN-III (PASylated IL-28A, XL-protein GmbH) was generated to prolong the plasma half-life of IFN-III. Pharmacologic activity and the effects of PASylated IL-28A on radiation-induced thymus damage and the course of GVHD after allo-HSCT with myeloablative TBI were tested.

Results: The course and severity of GVHD after myeloablative TBI and allo-HSCT in IL-28Ra mice was comparable to those in WT mice. Activation of the IFN-III pathway by PASylated IL-28A did not significantly modulate GVHD after allo-HSCT with TBI. Furthermore, IL28Ra mice and WT mice showed similar thymus regeneration after radiation, which could also not be significantly modulated by IFN-III receptor engagement using PASylated IL-28A.

Conclusions: We analyzed the role of IFN-III signaling during radiation-mediated acute tissue injury. Despite molecular and biologic homologies with IFN-I and IL-22, IFN-III signaling did not improve thymus regeneration after radiation or the course of GVHD after myeloablative TBI and allo-HSCT.
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http://dx.doi.org/10.1016/j.ijrobp.2018.11.038DOI Listing
March 2019

Targeting RIG-I or STING promotes epithelial regeneration.

Oncotarget 2017 Dec 6;8(70):114418-114419. Epub 2017 Dec 6.

Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Klinik und Poliklinik für Innere Medizin 3, Hämatologie und Onkologie, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

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http://dx.doi.org/10.18632/oncotarget.22994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777698PMC
December 2017

A20 deletion in T cells modulates acute graft-versus-host disease in mice.

Eur J Immunol 2017 11 15;47(11):1982-1988. Epub 2017 Sep 15.

Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

The NF-κB regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4 and CD8 donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T-cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-γ and systemic inflammation was elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20 T cells. Still, A20-deficient T cells, activated either through T cell receptor-dependent or -independent mechanisms, were less viable than control A20 T cells, highlighting that A20 balances both, T-cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T-cell-mediated inflammatory diseases like GVHD.
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http://dx.doi.org/10.1002/eji.201646911DOI Listing
November 2017

RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury.

Sci Transl Med 2017 04;9(386)

III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

The molecular pathways that regulate the tissue repair function of type I interferon (IFN-I) during acute tissue damage are poorly understood. We describe a protective role for IFN-I and the RIG-I/MAVS signaling pathway during acute tissue damage in mice. Mice lacking mitochondrial antiviral-signaling protein (MAVS) were more sensitive to total body irradiation- and chemotherapy-induced intestinal barrier damage. These mice developed worse graft-versus-host disease (GVHD) in a preclinical model of allogeneic hematopoietic stem cell transplantation (allo-HSCT) than did wild-type mice. This phenotype was not associated with changes in the intestinal microbiota but was associated with reduced gut epithelial integrity. Conversely, targeted activation of the RIG-I pathway during tissue injury promoted gut barrier integrity and reduced GVHD. Recombinant IFN-I or IFN-I expression induced by RIG-I promoted growth of intestinal organoids in vitro and production of the antimicrobial peptide regenerating islet-derived protein 3 γ (RegIIIγ). Our findings were not confined to RIG-I/MAVS signaling because targeted engagement of the STING (stimulator of interferon genes) pathway also protected gut barrier function and reduced GVHD. Consistent with this, STING-deficient mice suffered worse GVHD after allo-HSCT than did wild-type mice. Overall, our data suggest that activation of either RIG-I/MAVS or STING pathways during acute intestinal tissue injury in mice resulted in IFN-I signaling that maintained gut epithelial barrier integrity and reduced GVHD severity. Targeting these pathways may help to prevent acute intestinal injury and GVHD during allogeneic transplantation.
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http://dx.doi.org/10.1126/scitranslmed.aag2513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604790PMC
April 2017

Card9 controls Dectin-1-induced T-cell cytotoxicity and tumor growth in mice.

Eur J Immunol 2017 05 10;47(5):872-879. Epub 2017 Apr 10.

Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität, Munich, Germany.

Activation of the C-type lectin receptor Dectin-1 by β-glucans triggers multiple signals within DCs that result in activation of innate immunity. While these mechanisms can potently prime CD8 cytotoxic T-cell (CTL) responses without additional adjuvants, the Dectin-1 effector pathways that control CTL induction remain unclear. Here we demonstrate that Dectin-1-induced CTL cross-priming in mice does not require inflammasome activation but strictly depends on the adapter protein Card9 in vitro. In vivo, Dectin-1-mediated Card9 activation after vaccination drives both expansion and activation of Ag-specific CTLs, resulting in long-lasting CTL responses that are sufficient to protect mice from tumor challenge. This Dectin-1-induced antitumor immune response was independent of NK cell function and completely abrogated in Card9-deficient mice. Thus, our results demonstrate that Dectin-1-triggered Card9 signaling but not inflammasome activation can potently cross-prime Ag-specific CTLs, suggesting that this pathway would be a candidate for immunotherapy and vaccine development.
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http://dx.doi.org/10.1002/eji.201646775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434796PMC
May 2017

Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets.

J Immunol 2017 04 10;198(7):2747-2759. Epub 2017 Feb 10.

III. Medizinische Klinik für Hämatologie und Onkologie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany;

NKT cells represent a small subset of glycolipid-recognizing T cells that are heavily implicated in human allergic, autoimmune, and malignant diseases. In the thymus, precursor cells recognize self-glycolipids by virtue of their semi-invariant TCR, which triggers NKT cell lineage commitment and maturation. During their development, NKT cells are polarized into the NKT1, NKT2, and NKT17 subsets, defined through their cytokine-secretion patterns and the expression of key transcription factors. However, we have largely ignored how the differentiation into the NKT cell subsets is regulated. In this article, we describe the mRNA-binding Roquin-1 and -2 proteins as central regulators of murine NKT cell fate decisions. In the thymus, T cell-specific ablation of the Roquin paralogs leads to a dramatic expansion of NKT17 cells, whereas peripheral mature NKT cells are essentially absent. Roquin-1/2-deficient NKT17 cells show exaggerated lineage-specific expression of nearly all NKT17-defining proteins tested. We show through mixed bone marrow chimera experiments that NKT17 polarization is mediated through cell-intrinsic mechanisms early during NKT cell development. In contrast, the loss of peripheral NKT cells is due to cell-extrinsic factors. Surprisingly, Roquin paralog-deficient NKT cells are, in striking contrast to conventional T cells, compromised in their ability to secrete cytokines. Altogether, we show that Roquin paralogs regulate the development and function of NKT cell subsets in the thymus and periphery.
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http://dx.doi.org/10.4049/jimmunol.1601732DOI Listing
April 2017

Continuous T cell receptor signals maintain a functional regulatory T cell pool.

Immunity 2014 Nov 6;41(5):722-36. Epub 2014 Nov 6.

Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Department of Hematology, Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 15, 81675 Munich, Germany. Electronic address:

Regulatory T (Treg) cells maintain immune homeostasis and prevent inflammatory and autoimmune responses. During development, thymocytes bearing a moderately self-reactive T cell receptor (TCR) can be selected to become Treg cells. Several observations suggest that also in the periphery mature Treg cells continuously receive self-reactive TCR signals. However, the importance of this inherent autoreactivity for Treg cell biology remains poorly defined. To address this open question, we genetically ablated the TCR of mature Treg cells in vivo. These experiments revealed that TCR-induced Treg lineage-defining Foxp3 expression and gene hypomethylation were uncoupled from TCR input in mature Treg cells. However, Treg cell homeostasis, cell-type-specific gene expression and suppressive function critically depend on continuous triggering of their TCR.
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http://dx.doi.org/10.1016/j.immuni.2014.10.012DOI Listing
November 2014

The Nlrp3 inflammasome regulates acute graft-versus-host disease.

J Exp Med 2013 Sep 26;210(10):1899-910. Epub 2013 Aug 26.

Department of Dermatology, University Hospital, CH-8091 Zürich, Switzerland.

The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome-mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro-IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication.
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http://dx.doi.org/10.1084/jem.20130084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782050PMC
September 2013
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