The Beilhack Lab

The Beilhack lab at the Würzburg University Hospital and Julius-Maximilians-University Würzburg has been recognized with a prestigious research award for pioneering a novel concept in cancer therapy. The award was presented as part of the annual funding initiative by “Forschung hilft”, the Foundation for Cancer Research in Würzburg, Germany, which distributed €221,000 to 19 groundbreaking oncology projects this year.

The Beilhack lab’s innovative work, supported by a grant of €14,000, focuses on advancing immune-targeted therapies, a promising field in the fight against cancer. The recognition highlights the lab’s dedication to developing cutting-edge treatments that aim to improve patient outcomes and shape the future of oncology.

At the awards ceremony on November 29, Gabriele Nelkenstock, Chairwoman of the Foundation, emphasized the importance of supporting visionary projects: “These awards provide vital momentum for breakthrough research, while also recognizing the outstanding contributions of our scientists.”

For more information about the awarded projects and the foundation’s mission visit www.forschung-hilft.de.

Haroon Shaikh, PhD from the lab of Prof. Andreas Beilhack at University Hospital Würzburg received the distinguished EBMT Basic Science Award 2024 for groundbreaking findings on how blood vessel cells in lymph nodes trigger the feared alloreactive T-cell response after hematopoietic cell transplantation. This discovery paves the way for innovative therapies against acute Graft-versus-Host Disease (GvHD).

At the 50th European Congress of the European Society for Blood and Marrow Transplantation (EBMT) in Glasgow, Dr. Haroon Shaikh was honored with the prestigious EBMT Basic Science Award 2024. Representing the Beilhack lab at the University Hospital Würzburg and our DFG TRR221 GvH-GvL consortium Erlangen-Regenburg-Würzburg, Dr. Shaikh uncovered that blood vessel cells in lymph nodes activate alloreactive CD4+ T cells, thereby initiating acute GvHD.

This discovery offers new avenues for treating patients post-allogeneic stem cell transplantation. “A series of rigorous experiments revealed that endothelial cells in lymph node blood vessels can trigger the dangerous immune response,” explained Dr. Shaikh. “These findings present several new therapeutic strategies to enhance leukemia patient outcomes.”

Dr. Shaikh’s award-winning research, titled “Lymph Node Blood Endothelial Cells Prime Alloreactive CD4+ T Cells in Acute Graft-Versus-Host Disease Initiation,” was recognized for its outstanding contribution at the EBMT Congress. Alongside the Basic Science Award, Dr. Shaikh also earned the Young Investigator Award, while his colleague Juan Gamboa Vargas, also from the Beilhack lab received a Best Young Abstract Poster Award.

“These accolades underscore the vital importance of basic research in preclinical models and patient sample analysis for enhancing current therapies and devising entirely new treatment strategies,” said Prof. Beilhack. “The Basic Science Award is especially motivating for our team, and it is an invaluable boost for Dr. Shaikh as he embarks on establishing his own research group.”

Prof. Hermann Einsele, Director of the Department of Medicine II, and speaker at Würzburg University Hospital for the DFG-funded Collaborative Research Center Transregio 221 “GvH-GvL,” commented: “Being awarded this prestigious European research prize for the second time in three years validates that we are on the right path to significantly advancing cancer immunotherapy.”

Building on the new discovery, the research team plans to pursue three new directions based on these findings: examining similar blood vessel cells in the bone marrow for targeted immune responses against cancer, investigating whether lymph node endothelial cells also present antigens from surrounding organs to alloreactive T cells, and exploring strategies to alter antigen presentation by lymph node blood vessels to prevent acute GvHD in patients. Image courtesy © EBMT

Link to the interview with Dr. Haroon Shaikh at the  EBMT TV Studio.

For more information, visit the press release in German.

The ongoing research  project is being funded by the German Research Council (DFG) research consortium TRR221 GvH-GvL at the Bavarian partner Universities of Erlangen, Regensburg and Würzburg.

The Beilhack and Wajant labs at Würzburg University Hospital have achieved a significant milestone in immunotherapy. Our latest study reveals innovative design principles for antibody-based TNFR2 agonists that operate independently of FcγR, marking a substantial advancement in treating autoimmune diseases and cancer.

In a succession of groundbreaking studies, our interdisciplinary research teams have unveiled novel design principles for antibody-based therapeutics targeting TNFR2. These innovative constructs activate TNFR2 independently of FcγR, overcoming limitations of traditional antibodies. This development promises safer and more effective treatments for autoimmune diseases, graft-versus-host disease, organ rejection, neurodegenerative disorders, and cancer.

Harald Wajant’s research team together with scientists from the Beilhack lab identified domain architecture as crucial for creating FcγR-independent TNFR2 agonists. By strategically positioning TNFR2 binding sites on antibody scaffolds, we developed constructs with strong intrinsic agonistic activity.

In a series of studies we show that anti-TNFR2 antibodies with binding sites on opposing sides of the scaffold or with six or more TNFR2 binding sites exhibit robust FcγR-independent agonism. This approach bypasses the need for FcγR engagement for maximal activity.

Our new antibody formats selectively activate TNFR2, promising therapeutic benefits for autoimmune diseases, neurodegenerative conditions, and cancer. These novel biologicals avoid the unpredictable outcomes of FcγR-dependent activation, enhancing safety and efficacy for clinical use.

This research provides a blueprint for developing TNFR2-specific agonists, simplifying the creation of therapeutic antibodies. By focusing on optimal domain architecture rather than traditional characteristics like epitope recognition and affinity, our study accelerates the path from research to clinical application. Potent TNFR2 agonists can now be generated from nearly any TNFR2-specific antibody, paving the way for precise and effective immunotherapies.

Patients with autoimmune and inflammatory diseases, neurodegenerative disorders, and cancer can greatly benefit from these advancements. The new TNFR2 agonists enhance Treg activation and expansion, promoting immune regulation and tissue homeostasis. Additionally, they hold promise for restoring anti-tumor immunity by co-stimulating CD8⁺ T-cells, potentially leading to more effective cancer treatments.

Our research team plans further preclinical and clinical evaluations to explore the full potential of these FcγR-independent TNFR2 agonists. These studies will assess their efficacy in various disease models and determine optimal therapeutic settings. 

References:

Anany MA, Haack S, Lang I, Dahlhoff J, Gamboa Vargas J, Steinfatt T, Päckert L, Weisenberger D, Zaitseva O, Medler J, Kucka K, Zhang T, Van Belle T, van Rompaey L, Beilhack A*, Wajant H*. (2024). Generic design principles for antibody-based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism. Theranostics 14(2):496-509.

Gamboa Vargas J*, Wagner J*, Shaikh H, Lang I, Medler J, Anany M, Steinfatt T, Peña Mosca J, Haack S, Dahlhoff J, Büttner-Herold M, Graf C, Arellano E, Einsele H, Wajant H*, Beilhack A*. (2022). A TNFR2-specific TNF fusion protein with improved in vivo activity. Front Immunol 13:888274.

Wajant H*, Beilhack A*. (2019). Targeting Regulatory T Cells by Addressing Tumor Necrosis Factor and Its Receptors in Allogeneic Hematopoietic Cell Transplantation and Cancer. Front Immunol 10: 2040.

Chopra M, Biehl M, Steinfatt T, Brandl A, Kums J, Amich J, Vaeth M, Kuen J, Holtappels R, Podlech J, Mottok A, Kraus S, Jordán Garrote AL, Bäuerlein CA, Brede C, Ribecchini E, Fick A, Seher A, Polz J, Ottmüller K, Baker J, Nishikii H, Ritz M, Mattenheimer K, Schwinn S, Winter T, Schäfer V, Krappmann S, Einsele H, Mueller TD, Reddehase MJ, Lutz MB, Männel DN, Berberich-Siebelt F, Wajant H*, Beilhack A*. (2016). Exogenous TNFR2 activation protects from acute GvHD by induction of host Treg expansion. J Exp Med 213:1881–1900.

Cells move from the brain to the gut and back. – A new paper by Rhonda McFleder et al. reveals a groundbreaking discovery in the intricate world of brain-gut communication. Published in “Nature Communications,” the study challenges the conventional wisdom that communication between the brain and the gut is a one-way street.

“In our latest study, we demonstrate that brain-to-gut communication is a dynamic two-way process. Cells can migrate from the brain to the gut, influencing the spread of diseases,” explains neurobiologist Professor Rhonda McFleder, who lead the study alongside Professor Chi Wang Ip.

The research focuses on the role of immune cells, particularly macrophages, in the progression of Parkinson’s disease. The team discovered that proteins linked to Parkinson’s, specifically α-Synuclein (αSyn), migrate from the brain to the gut, causing disruptions. Notably, these protein accumulations were found in macrophages, not the neurons controlling the gut’s autonomous nervous system.

“To definitively test the migration of macrophages from the brain to the gut, we developed a method to label brain cells and track their migration,” says Rhonda McFleder, who teamed up with the Beilhack lab to uncover a unique communication between the brain and gut, suggesting its involvement in Parkinson’s disease spread.

Professor Chi Wang Ip adds a crucial finding: “We observed that macrophages not only migrate in Parkinson’s but also under control conditions, broadening the relevance to other neurological diseases. Just as these cells drive pathology in Parkinson’s, they may also promote disease spread in other neurological conditions.”

Next steps involve fully characterizing these migrating cells and identifying homing molecules guiding them to the gut. “Once identified, we can develop therapeutics targeting these molecules, potentially halting the progression of Parkinson’s and other neurological diseases,” says Rhonda McFleder.

The study involved collaboration from various research groups and received support from the Alexander von Humboldt Foundation, the Bavarian Ministry of Economic Affairs, the German Research Foundation (DFG), the Interdisciplinary Center for Clinical Research (IZKF) at the University of Würzburg, the VERUM Foundation, and the former EU Horizon 2020 research and innovation program.

McFleder RL, Makhotkina A, Groh J, Keber U, Imdahl F, Peña Mosca J, Peteranderl A, Wu J, Tabuchi S, Hoffmann J, Karl AK, Pagenstecher A, Vogel J, Beilhack A, Koprich JB, Brotchie JM, Saliba AE, Volkmann J, Ip CW. (2023). Brain-to-gut trafficking of alpha-Synuclein by CD11c+ cells in a mouse model of Parkinson’s disease. Nature Communications, 14(1):7529.

This research article was also highlighted in Nature Reviews Neurology.

Link to press release from Würzburg University Hospital, Germany (in German).

Dr. Stefanie Schwinn, who specialized in her experimental medical thesis in Group 3 Medulloblastoma, was honored with the prestigious Klug & Sichler Doctoral Prize in Cancer Research by the Faculty of Medicine at the University of Würzburg on Monday at this year’s Dies Academicus.

As a dedicated doctoral candidate under the mentorship of Prof. Matthias Wölfl at the University Children’s Hospital and Prof. Andreas Beilhack at the Department of Medicine II, Dr. Schwinn embarked on extensive research to explore innovative treatment options for the highly aggressive subgroup of pediatric brain tumors known as Molecular Subgroup 3 Medulloblastoma. Her groundbreaking work led to the discovery of a highly effective treatment combination – Gemcitabine, a cytostatic agent, along with Axitinib, a VEGF receptor inhibitor – against Medulloblastoma cells. To closely mimic patient conditions, she conducted her experiments with exceptional skill and dedication on a demanding mouse model, employing advanced techniques such as light sheet fluorescence microscopy (LSFM).

The results unveiled that Dr. Schwinn’s chosen treatment option was not only at least as effective as the standard therapy but also better tolerated. Her pioneering research was published as the lead author in the journal Scientific Reports. Additionally, Dr. Schwinn contributed as a co-author to eight more scientific publications in the field of experimental oncology.

Dr. Stefanie Schwinn’s exceptional work has made a significant contribution to the development of potential therapy approaches for children with this highly aggressive brain tumor. Her findings now provide a solid foundation for clinical research and hold the potential to enhance treatment options for this patient group.

A new study published today in Nature Communications uncovers that the cytokine GDF-15 inhibits T cell infiltration into tumors, opening up promising new pathways for cancer therapy. Researchers from Würzburg University Hospital and the biotech spin-off CatalYm have demonstrated that high GDF-15 levels predict resistance to PD-1-based immune checkpoint blockade therapy. Neutralizing GDF-15 in preclinical mouse models of GDF-15-expressing cancers significantly boosted T cell infiltration and enhanced the therapeutic efficacy of immune checkpoint blockade. This discovery offers a promising target for enhancing the efficacy of immunotherapy across various types.

For more information, visit the press release in German.

Publication Reference:

Haake M, Haack B, Schäfer T, Harter PN, Mattavelli G, Eiring P, Vashist N, Wedekink F, Genssler S, Fischer B, Dahlhoff J, Mokthari F, Kuzkina A, Welters MJP, Benz TM, Sorger L, Thiemann V, Amanzar G, Selle M, Thein K, Späth J, Gonzalez MC, Reitinger C, Ipsen-Escobedo A, Wistuba-Hamprecht K, Eichler K, Filipski K, Zeiner PS, Beschorner R, Goedemans R, Gogolla FH, Hackl H, Rosswinkel RW, Thiem A, Romer Roche P, Joshi H, Pühringer D, Wöckel A, Diessner JE, Rüdiger M, Leo E, Cheng PF, Levesque PFP, Goebeler M, Sauer M, Nimmerjahn F, Schuberth-Wagner C, Von Felten S, Mittelbronn M, Mehling M, Beilhack A, van der Burg SH, Riedel A, Weide B, Dummer R, Wischhusen J. (2023). Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nature Communications 14(1):4253.

In a new study published in the prestigious journal Cell Metabolism, lead author Theresa Manzo supported by an international research team unveiled key findings that could revolutionize cancer immunotherapy. The study highlights the profound impact of linoleic acid on cytotoxic T cells, showcasing its potential to enhance the effectiveness of antitumor immune responses.

Recently it has been recognized that the metabolic state of CD8+ cytotoxic T cells is a key player in the immune response against tumors. Our interdisciplinary team, in this project under the leadership of Theresa Manzo,   discovered that specific lipids, when improperly regulated, can compromise CD8+ T cell mitochondrial integrity, leading to impaired antitumor responses. Notably, the newly published study demonstrates that linoleic acid emerges as a major positive regulator, bolstering CD8+ T cell activity and overcoming metabolic hurdles. By mitigating exhaustion, cytotoxic CD8+ T cells become capable of sustaining potent and prolonged antitumor responses, offering new possibilities for overcoming challenges in cancer treatment.

The study also shed light on the ability of linoleic acid to induce a memory-like phenotype in CD8+ T cells. This transformation equips the cells with superior effector functions, suggesting that linoleic acid treatment could play a crucial role in enhancing the longevity and effectiveness of immune responses against cancer. A deeper exploration into cellular dynamics revealed that linoleic acid treatment enhances the formation of ER-mitochondria contacts. This action promotes calcium (Ca2+) signaling, optimizes mitochondrial energetics, and boosts the effector functions of CD8+ T cells. 

As linoleic acid-instructed CD8+ T cells exhibited superior antitumor potency both in vitro and in vivo, this new study suggests linoleic acid treatment as an enhancer for more effective adoptive cellular immunotherapy against cancer. 

This work was supported by our German Research Council (DFG) research consortium  TRR221 GvH-GvL.

Reference:

Nava Lauson CB, Tiberti S, Corsetto P, Conte F, Punit T, Machwirth M, Ebert S, Loffreda A, Scheller L, Mokhtari Z, Sheta D, Peters T, Raman AT, Greco F, Rizzo A, Beilhack A, Signori G, Tumino N, Vacca P, McDonnell L, Raimondi A, Greenberg PD, Huppa JB, Cardaci S, Caruana I, Rodighiero S, Nezi L, Manzo T. (2023). Linoleic acid potentiates CD8+ T cell metabolic fitness and anti-tumor immunity. Cell Metabolism 35(4):633-650.e9.

Today, Haroon Shaikh unveils in a new publication in the Journal of Clinical Investigation Insight a critical mechanism by which fibroblastic reticular cells (FRCs) mitigate acute graft-versus-host disease (aGvHD). Our study identifies how FRCs maintain regulatory T cells (Tregs) by providing T cell receptor signals via MHC class II (MHCII) surface molecules to regulate aGvHD, a severe complication following allogeneic hematopoietic cell transplantation (allo-HCT).

Our team investigated the function of MHCII on Ccl19+ FRCs in shaping the donor CD4+ T cell response during aGvHD. We found that mice lacking MHCII expression on these FRCs experienced exacerbated aGvHD, characterized by aberrant CD4+ T cell activation and significantly reduced Treg and invariant NK T (iNKT) cell expansion. This imbalance led to a loss of protection from aGvHD, even when donor Tregs were adoptively transferred.

Interestingly, while FRCs could process and present antigens and upregulate costimulatory receptors, they were not necessary for the initial activation of alloreactive CD4+ T cells. Instead, their critical role was in the maintenance and proliferation of Tregs during the effector phase of aGvHD, highlighting their immunoprotective function.

This discovery underscores the importance of FRCs in creating a supportive niche for Tregs in secondary lymphoid organs (SLOs). By maintaining Tregs through MHCII-mediated interactions, FRCs help regulate alloimmune responses, offering a potential therapeutic target for aGvHD treatment.

Why these new findings matter
Our research results provide new insights into the cellular and molecular interactions that govern immune responses in aGvHD. Understanding the role of FRCs in Treg maintenance opens up possibilities for novel therapeutic strategies, such as targeting FRCs to enhance Treg function and improve patient outcomes after allo-HCT. Our study’s findings pave the way for future exploration into the adoptive transfer of FRCs or direct targeting of these cells to mitigate aGvHD, offering hope for more effective and patient tailored treatments.

The study resulted from the interdisciplinary collaboration of research teams at Würzburg University Hospital and academic partners from Erlangen, Braunschweig in Germany, Lausanne, St. Gallen and Zurich in Switzerland. The work was supported by our German Research Council (DFG) research consortium TRR221 GvH-GvL.

Reference:

Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Peña Mosca J, Arellano Viera E, Kern MAG, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. (2022). Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 7(22):e154250. 

A pioneering study published in Immunity today reveals how tissue-specific unconventional T cells travel via lymphatic pathways to lymph nodes, where they orchestrate customized immune responses. This breakthrough has profound implications for targeted vaccination and immunotherapy strategies.

Unconventional T cells, including invariant natural killer T cells, gamma delta T cells, and mucosal-associated invariant T cells, differ from conventional T cells by engaging in broader immune surveillance and responding to diverse signals, such as stress signals, lipid antigens, or metabolites.

“Our study demonstrates that local forces guide unconventional T cells from tissues to lymph nodes, where they imprint tissue-specific characteristics,” explains our collaboration partner Prof. Wolfgang Kastenmüller, who lead the international research team.” Dendritic cells have long been known to relay information from peripheral tissues to draining lymph nodes, initiating immune responses. However, it’s now evident that dendritic cells are not solely responsible for this crucial flow of information.  Each tissue harbors unique subtypes of unconventional T cells, influencing the composition and function of T cells in nearby lymph nodes.”

This diversity leads to varied immune responses within lymph nodes, where unconventional T cells form interconnected functional units across different T cell receptor-based lineages. These units are crucial for shaping both innate and adaptive immune responses tailored to the specific tissues drained by each lymph node.

Implications for Future Research and Medicine

Understanding how unconventional T cells migrate and function in lymph nodes is pivotal for advancing immunology and medical practice. Leveraging our insights allows scientists to enhance tissue-specific immune responses, paving the way for precision vaccination and immunotherapy approaches with reduced side effects. This progress holds promise for personalized medicine, facilitating more effective treatments that meet individual patient needs while minimizing adverse effects.

This interdisciplinary research project was led by Prof. Wolfgang Kastenmüller at Würzburg’s Institute for Systems Immunology at the Julius-Maximilians-University Würzburg, in collaboration with groups from the Würzburg Helmholtz Institute for RNA-based Infection Research (HIRI), the JMU Institute for Molecular Infection Biology (IMIB), the Centre d’Immunologie de Marseille-Luminy (CIML), and our team at the Department of Medicine II at Würzburg University Hospital. Financial support was provided by IZKF Würzburg, the German Research Foundation (DFG), the European Research Council (ERC), and the Max Planck Society.

For more information, visit the press release in German.

Publication Reference:

Ataide MA*, Knöpper K*, Cruz de Casas P*, Ugur M, Eickhoff S, Zou M, Shaikh H, Trivedi A, Grafen A, Yang T, Prinz I, Ohlsen K, Gomez de Agüero M, Beilhack A, Huehn J, Gaya M, Saliba AE, Gasteiger G, Kastenmüller W. (2022). Lymphatic migration of unconventional T cells promotes site-specific immunity in distinct lymph nodes. Immunity, 55(10):1813-1828.e9.

This research article was also highlighted in Immunity by Emily Thornton and Tal Arnon: “It takes a village to skew a lymph node.“

The running team of the Beilhack lab joined the Würzburg Marathon 2022. Alltogether 16 teams of the University Hospital participated in this sportive event to raise awareness and donations for cancer research.