Publications by authors named "Lukas F Mager"

7 Publications

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Impact of the microbiome on tumor immunity.

Curr Opin Immunol 2021 Feb 26;69:39-46. Epub 2021 Feb 26.

Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.

The microbiome is a potent modulator of host immune responses and over the past years has been shown to impact tumor immunology. Both pro-tumorigenic and anti-tumorigenic functions have been associated with the microbiome and functional studies have pinpointed specific anti-tumor immunity-promoting microbes, such as Akkermansia muciniphila and Bifidobacterium longum. The identification of key host genes and microbe-derived signals involved in anti-tumor immunity is still in its infancy. Here we focus on recent advances in this area, revealing host molecules found to be central in host-microbiome dependent modulation of tumor immunity, and highlight key questions to be tackled in the field.
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http://dx.doi.org/10.1016/j.coi.2021.01.002DOI Listing
February 2021

Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.

Science 2020 09 13;369(6510):1481-1489. Epub 2020 Aug 13.

Department of Physiology and Pharmacology, Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada.

Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species-, , and species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.
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http://dx.doi.org/10.1126/science.abc3421DOI Listing
September 2020

The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer.

Mucosal Immunol 2019 07 5;12(4):990-1003. Epub 2019 Jun 5.

Institute of Pathology, University of Bern, Bern, Switzerland.

The composition of immune infiltrates strongly affects the prognosis of patients with colorectal cancer (CRC). Interleukin (IL)-33 and regulatory T cells (Tregs) in the tumor microenvironment have been separately implicated in CRC; however their contribution to intestinal carcinogenesis is still controversial. Here, we reveal that IL-33 signaling promotes CRC by changing the phenotype of Tregs. In mice with CRC, tumor-infiltrating Tregs preferentially upregulate IL-33 receptor (ST2), and IL-33/ST2 signaling positively correlates with tumor number and size. Transcriptomic and flow cytometry analyses demonstrate that ST2 expression induces a more activated and migratory phenotype in FOXP3 Tregs, which favors their accumulation in the tumor environment. Consequently, genetic ablation of St2 reduces Treg infiltration and concomitantly enhances the frequencies of effector CD8 T cells, thereby restraining CRC. Mechanistically, IL-33 curtails IL-17 production by FOXP3 Tregs and inhibits Th17 differentiation. In humans, numbers of activated ST2-expressing Tregs are increased in blood and tumor lesions of CRC patients, suggesting a similar mode of regulation. Together, these data indicate a central role of IL-33/ST2 signaling in shaping an immunosuppressive environment during intestinal tumorigenesis. Blockade of this pathway may provide a strategy to modulate the composition of CRC immune infiltrates.
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http://dx.doi.org/10.1038/s41385-019-0176-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746527PMC
July 2019

Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice.

EBioMedicine 2018 May 5;31:66-78. Epub 2018 Apr 5.

Christian Doppler Laboratory for Immunomodulation, 1090 Vienna, Austria; Institute of Immunology, Medical University of Vienna, 1090 Vienna, Austria. Electronic address:

Background: Immunoglobulin(Ig)E-associated allergies result from misguided immune responses against innocuous antigens. CD4 T lymphocytes are critical for initiating and perpetuating that process, yet the crucial factors determining whether an individual becomes sensitized towards a given allergen remain largely unknown.

Objective: To determine the key factors for sensitization and allergy towards a given allergen.

Methods: We here created a novel human T cell receptor(TCR) and human leucocyte antigen (HLA)-DR1 (TCR-DR1) transgenic mouse model of asthma, based on the human-relevant major mugwort (Artemisia vulgaris) pollen allergen Art v 1 to examine the critical factors for sensitization and allergy upon natural allergen exposure via the airways in the absence of systemic priming and adjuvants.

Results: Acute allergen exposure led to IgE-independent airway hyperreactivity (AHR) and T helper(Th)2-prone lung inflammation in TCR-DR1, but not DR1, TCR or wildtype (WT) control mice, that was alleviated by prophylactic interleukin(IL)-2-αIL-2 mAb complex-induced expansion of Tregs. Chronic allergen exposure sensitized one third of single DR1 transgenic mice, however, without impacting on lung function. Similar treatment led to AHR and Th2-driven lung pathology in >90% of TCR-DR1 mice. Prophylactic and therapeutic expansion of Tregs with IL-2-αIL-2 mAb complexes blocked the generation and boosting of allergen-specific IgE associated with chronic allergen exposure.

Conclusions: We identify genetic restriction of allergen presentation as primary factor dictating allergic sensitization and disease against the major pollen allergen from the weed mugwort, which frequently causes sensitization and disease in humans. Furthermore, we demonstrate the importance of the balance between allergen-specific T effector and Treg cells for modulating allergic immune responses.
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http://dx.doi.org/10.1016/j.ebiom.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014064PMC
May 2018

Cytokine-Induced Modulation of Colorectal Cancer.

Front Oncol 2016 19;6:96. Epub 2016 Apr 19.

Institute of Pathology, University of Bern , Bern , Switzerland.

The emergence of novel immunomodulatory cancer therapies over the last decade, above all immune checkpoint blockade, has significantly advanced tumor treatment. For colorectal cancer (CRC), a novel scoring system based on the immune cell infiltration in tumors has greatly improved disease prognostic evaluation and guidance to more specific therapy. These findings underline the relevance of tumor immunology in the future handling and therapeutic approach of malignant disease. Inflammation can either promote or suppress CRC pathogenesis and inflammatory mediators, mainly cytokines, critically determine the pro- or anti-tumorigenic signals within the tumor environment. Here, we review the current knowledge on the cytokines known to be critically involved in CRC development and illustrate their mechanisms of action. We also highlight similarities and differences between CRC patients and murine models of CRC and point out cytokines with an ambivalent role for intestinal cancer. We also identify some of the future challenges in the field that should be addressed for the development of more effective immunomodulatory therapies.
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http://dx.doi.org/10.3389/fonc.2016.00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835502PMC
May 2016

The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice.

Oncoimmunology 2016;5(1):e1062966. Epub 2015 Jun 26.

Institute of Pathology, University of Bern , Bern, Switzerland.

Colorectal cancer (CRC) develops through a multistep process and is modulated by inflammation. However, the inflammatory pathways that support intestinal tumors at different stages remain incompletely understood. Interleukin (IL)-33 signaling plays a role in intestinal inflammation, yet its contribution to the pathogenesis of CRC is unknown. Using immunohistochemistry on 713 resected human CRC specimens, we show here that IL-33 and its receptor ST2 are expressed in low-grade and early-stage human CRCs, and to a lesser extent in higher-grade and more advanced-stage tumors. In a mouse model of CRC, ST2-deficiency protects from tumor development. Moreover, bone marrow (BM) chimera studies indicate that engagement of the IL-33/ST2 pathway on both the radio-resistant and radio-sensitive compartment is essential for CRC development. Mechanistically, activation of IL-33/ST2 signaling compromises the integrity of the intestinal barrier and triggers the production of pro-tumorigenic IL-6 by immune cells. Together, this data reveals a tumor-promoting role of IL-33/ST2 signaling in CRC.
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http://dx.doi.org/10.1080/2162402X.2015.1062966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760343PMC
June 2015

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms.

J Clin Invest 2015 Jul 26;125(7):2579-91. Epub 2015 May 26.

Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell-derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33-expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34+ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.
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http://dx.doi.org/10.1172/JCI77347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4563674PMC
July 2015