JAM-C as a switch for multiple myeloma dissemination

A new study, published by Andreas Brandl and our team in Blood Advances today, reveals that Junctional Adhesion Molecule C (JAM-C) plays a critical role in the progression and dissemination of multiple myeloma (MM), marking a significant advancement in our understanding of this aggressive blood cancer.
Junctional Adhesion Molecule C, JAM-C (JAM-3) responsible for MM dissemination. JAM-C positive multiple myeloma cells down regulate CD138. JAM-C identifies CD138 negative myeloma cells, which would be missed in analyses after CD138  enrichment. Andreas Beilhack laboratory at Immunotherapy program at Würzburg University, Germany, NCT WERA National Cancer Center

Reciprocal regulation of JAM-C and CD138 switches programs in multiple myeloma cells. Brandl A. et al. Blood Advances 2022

In an interdisciplinary approach, senior scientist Andreas Brandl, PhD, and colleagues have discovered that JAM-C specifically marks a subset of MM cells with low or absent CD138 expression (CD138low/neg), distinguishing them within the bone marrow of both human patients and in MM mouse models. Targeting JAM-C in preclinical models showed a promising reduction in MM progression and dissemination, indicating that JAM-C inhibitors could complement existing treatments and offer new therapeutic avenues.

The study uncovered that JAM-C expression on MM cells correlates inversely with CD138, a canonical cell surface receptor associated with plasma cells. This inverse relationship pinpoints a potential mechanism through which MM cells transition between localized growth and widespread dissemination. Upregulation of JAM-C was observed to facilitate the migration and metastasis of MM cells, a crucial step in cancer spread. Blocking JAM-C in a murine model of MM led to a significant reduction in disease severity, MM dissemination and cancer burden.

Lead Researcher Dr. Andreas Brandl states, “Our research shows that targeting JAM-C could be a pivotal strategy in controlling multiple myeloma progression. This could lead to more personalized and effective treatments for patients suffering from this challenging disease.” The scientist proposes that JAM-C could serve as both, a novel diagnostic biomarker and therapeutic target in MM. He envisions the development of treatments that specifically inhibit JAM-C, potentially enhancing patient outcomes when used alongside conventional therapies such as proteasome inhibitors and monoclonal antibodies.

The new findings result from a collaborative effort by scientists within the SPP consortium µbone of the German Research Council (DFG), the FORTITHER research network of the Bayerische Forschungsstiftung, the Interdisciplinary Center for Clinical Research Würzburg, and international research partners.

Reference:

Brandl A, Solimando AG, Mokhtari Z, Tabares P, Medler P, Manz H, Da Via M, Croci GA, Kurzwart M, Thusek S, Schneider T, Ebert R, Jakob F, Einsele H, Beilhack A. (2022). Junctional Adhesion Molecule-C expression specifies a CD138low/neg multiple myeloma cell population in mice and men. Blood Advances 6(7):2195-2206.

Multiple Myeloma Treatment through Targeted Treg Depletion

In a landmark study Dr. Julia Dahlhoff published in the journal Leukemia  a groundbreaking approach to combat multiple myeloma (MM). The paper from our team, titled “Transient Regulatory T-Cell Targeting Triggers Immune Control of Multiple Myeloma and Prevents Disease Progression,” uncovers the potential of briefly depleting regulatory T-cells (Tregs) to unleash the body’s own immune system to eradicate this challenging blood cancer.Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression. Julia Dahlhoff, PhD, Andreas Beilhack Lab, Würzburg University Hospital, Germany, Europe, Immunotherapy program targeting regulatory T cells

Multiple myeloma, characterized by the proliferation of malignant plasma cells in the bone marrow, often relapses due to the protective niche created by bone marrow-resident Tregs. The study reveals that Tregs not only cluster around malignant plasma cells but also support their survival and dissemination.

Using two syngeneic immunocompetent murine models, the team under the leadership of Prof. Andreas Beilhack demonstrated that temporary depletion of Tregs in mice with established MM led to a robust immune response, mediated by CD8 T cells and natural killer (NK) cells, resulting in complete and sustained remission of the disease.

“Targeting Tregs disrupts their suppressive grip on the immune system, allowing CD8 T cells and NK cells to attack and eliminate myeloma cells,” said Dr. Dahlhoff. “This short-term intervention effectively prevented MM progression and offers a new therapeutic strategy that minimizes the risk of autoimmunity.”

The study paves the way for developing Treg-targeted therapies, providing a novel avenue for treatment-resistant multiple myeloma.

Reference: 

Dahlhoff J, Manz H, Steinfatt T, Delgado-Tascon J, Seebacher E, Schneider T, Wilnit A, Mokhtari Z, Tabares P, Böckle D, Rasche L, Martin Kortüm K, Lutz MB, Einsele H, Brandl A, Beilhack A. (2022). Transient regulatory T cell targeting triggers immune control of multiple myeloma and prevents disease progression. Leukemia 36(3):790-800.

Young Investigator Award for Antonio Solimando

Former postdoctoral fellow and now young principal investigator at Bari University Dr. Antonio Solimando receives the IMS Young Investigator Award in Vienna, Austria.

Young Investigator Award for Antonio Solimando, 18th International Myeloma Workshop, Vienna 2021, Andreas Beilhack research lab, Würzburg UniversityClinician-Scientist Dr. Antonio Solimando will present our award winning research project on cell adhesion-regulated epithelial-mesenchymal-transition resulting in extramedullary multiple myeloma disease manifestation at the 18th International Myeloma Workshop in Vienna, Austria, on September 10th, 2021. This is a wonderful reward for our continuing fruitful scientific collaboration on the mechanisms and new therapeutic targets in adhesion mediated cancer progression. In the past years the basic science of this research project has been generously supported by the DFG µbone consortium and the therapeutic research aspects by the Bayerische Forschungsstiftung.

18th International Myeloma Workshop Vienna Austria, Young Investigator Award Group Picture 2021 Antonio Solimando, AG Beilhack Research Lab, Würzburg University, Germany

Image courtesy: International Myeloma Society

 

And the award goes to…

The European Society of Blood and Marrow Transplantation awarded our research on the protective function of host intestinal macrophages in acute graft-versus-host disease with this year’s Basic Science Award.

At the EBMT presidential symposium on March 15, 2021, postdoctoral fellow Dr. Duc-Dung Le presented our work and received this prestigious award together with his co-first author Dr. Ana-Laura Jordán Garrote on behalf of our entire team at University Hospital Würzburg and our national and international collaboration partners. Many thanks go to all the enthusiastic team members and especially to our partners within the DFG Transregio 221 consortium on GvH and GvL for the excellent support!

Read more about this award here.

Postdoctoral fellow Dr. Duc Dung Le receives EBMT Basic Science Award 2021 on behalf of the Beilhack lab
Prestigious research award to Dr. Duc Dung Le, Dr. Ana-Laura Jordán Garrote, Maria Ranecky and the entire team of the Beilhack lab and our collaboration partners of the DFG TRR221 consortium at Würzburg, Erlangen and Regensburg as well as Bern, Bonn, Harvard and Marseille.

Watch the interview with postdoctoral fellow Dr. Duc Dung Le here or on Youtube here.

A new potent approach to treat steroid-refractory acute Graft-versus-Host Disease?

Clinical studies suggested that endothelial dysfunction and damage can be involved in the development and severity of acute graft-versus-host disease (aGvHD), a complication in patients undergoing allogeneic hematopoietic cell transplantation. In a new paper under the lead of Olaf Penack from the Charité Berlin we show extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Subsequently, therapeutic intervention with an already clinical approved endothelium-protecting agent improved outcome in a mouse model of steroid-refractory aGvHD.

Sildenafil steroid-refractory acute GvHD, GvH-GvL, Andreas Beilhack laboratory, Würzburg University Immunology Program, Immunotherapy research Germany

Sildenafil protects from endothelial damage in experimental steroid-refractory acute GvHD

Allogeneic hematopoietic stem transplantation (allo-HCT) is the only curative treatment option for many patients suffering from blood cancers. However, there are still risks for patients undergoing allo-HCT. One major complication is acute graft-versus-host disease (aGvHD) occuring in more than two thirds of patients. This inflammatory condition primarily affecting the skin, liver, and intestines. Although treatment with steroids is successful in most patients, about the 20%-25% of patients fail initial steroid treatment resulting in a very high mortality rate. Currently, no standard treatment for this steroid-refractory aGVHD is available and its pathobiology remains poorly understood, thereby hindering the development of novel therapeutic approaches.

The endothelium is the first contact for immunological effector cells in the blood and a key regulator in various inflammatory processes. The endothelium was shown to be relevant for early complications after allo-HCT such as transplantation-associated-microangiopathy, veno-occlusive disease, capillary leak syndrome and diffuse alveolar hemorrhage. Recent studies also suggested a critical role of the endothelium in aGvHD. Accordingly, we found increased percentage of apoptotic Casp3+ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGvHD. 

Light sheet fluorescence microscopy, LSFM, Andreas Beilhack laboratory Würzburg University Immunology Program

Pathologic vascular restructuring in intestinal acute GvHD

In mouse models of experimental aGvHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. Employing light-sheet fluorescence microscopy revealed structural changes in the colonic vasculature including increased vessel branching and vessel diameter. Human biopsies and murine tissues from steroid refractory aGvHD revealed extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent steroid refractory aGvHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental steroid refractory aGvHD. The study by Steffen Cordes et al. demonstrates extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Consequently, therapeutic intervention by endothelium-protecting agents, such as sildenafil, appear attractive to treat steroid refractory aGvHD complementing current anti-inflammatory treatment options. 

 

This work resulted from a strong collaborative effort between clinicians and scientists from different European medical centers: The Charité Berlin and the University Hospitals of Barcelona (Spain), Hannover, Heidelberg and Würzburg. Our lab was supported for this study be the DFG collaborative research center TRR221 GvH-GvL (project B11).

 

Reference:

Cordes S, Mokhtari Z, Bartosova M, Mertlitz S, Riesner K, Shi Y, Mengwasser J, Kalupa M, McGeary A, Schleifenbaum J, Schrezenmeier J, Bullinger L, Diaz-Ricart M, Palomo M, Carrreras E, Beutel G, Schmitt CP, Beilhack A, Penack O. (2021). Endothelial damage and dysfunction in acute graft-versus-host disease. Haematologica 106(8):2147-2160.

Breaking a vicious cycle in multiple myeloma

Multiple myeloma is a malignant disease of antibody producing plasma cells. As this devastating type of cancer locates to the bones it seems that multiple myeloma highly depends on close interactions with the bone marrow microenvironment. In our new paper by clinician-scientist Dr. Antonio Solimando et al. we describe our new discovery that multiple myeloma cells use an adhesion molecule called JAM-A (Junctional-adhesion-molecule A) to interact with blood vessel lining endothelial cells. It appears as these endothelial-multiple myeloma interactions feed into a vicious cycle propagating disease progression.

Multiple myeloma, bone marrow environment, adhesion molecules, JAM-A, Andreas Beilhack laboratory, cancer immunotherapy, Antonio Solimando, vicious cycle, new treatment
Our projected started with our initial observation that the expression level of JAM-A by malignant plasma cells can predict disease outcome. Subsequently, we discovered that elevated membrane expression of JAM-A also on bone marrow endothelial cells of patients with newly diagnosed or relapsed-refractory multiple myeloma cells predicted poor clinical outcome.

Based on this finding we investigated how elevated JAM-A levels would contribute to more aggressive disease. We discovered that direct contact of endothelial cells with multiple myeloma cells would enhance JAM-A levels. Then it got even more interesting, as the cell adhesion molecule JAM-A has remarkable features: it can interact with itself if expressed on two opposing cell types. Furthermore, if JAM-A is shed by a cell, the soluble form of the JAM-A molecule can bind to cell-bound JAM-A, which in turn even enhances its binding capacity. What ensues is a vicious cycle of malignant plasma cells expressing and shedding JAM-A, increasing JAM-A expression on endothelial cells and stimulating blood vessel formation. In turn, increasing numbers of JAM-A-overexpressing endothelial cells can now better bind malignant plasma cells, which now find more interaction partners and by increasing the multiple myeloma niche space can produce more JAM-A. Consequently, using different experimental models we found that blocking the adhesion molecule JAM-A would inhibit blood vessel formation, reduce JAM-A interactions and impair multiple myeloma disease progression. These therapeutic effects of blocking JAM-A were observed in preclinical models not in patients and, therefore, must be interpreted with caution. Nevertheless, our new findings may point towards a potential Achilles’ heel of multiple myeloma that might be exploited therapeutically in the future.

This work was generally supported by the Bavarian Research Foundation within the research consortium FORTiTher and the German Research Council (DFG) consortium µbone.

Reference:

Solimando AG, Da Vià MC, Leone P, Borrelli P, Croci GA, Tabares P, Brandl A, Di Lernia G, Bianchi FP, Tafuri S, Steinbrunn T, Balduini A, Melaccio A, De Summa S, Argentiero A, Rauert-Wunderlich H, Frassanito MA, Ditonno P, Henke E, Klapper W, Ria R, Terragna C, Rasche L, Rosenwald A, Kortüm KM, Cavo M, Ribatti D, Racanelli V, Einsele H, Vacca A, Beilhack A. (2021). Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression. Haematologica 106(7):1943-1956.

Nature Reviews Microbiology features our recent research paper

Nature Reviews Microbiology, Andreas Beilhack lab, host-pathogen interactions, Würzburg University, Germany, Imaging, Light-sheet fluorescence microscopy, immunotherapyIn its current issue, the journal Nature Reviews Microbiology reports about our recent mBio research article advancing light-sheet fluorescence microscopy (LSFM) to study host-pathogen interactions within the 3D environment of the lung. In the news section Under the Lens, Manish S. Kushwah and Stephen Thorpe from Oxford University highlight our research article by former postdoctoral fellow Dr. Jorge Amich, postdoctoral fellow Zeinab Mokhtari et al. in their report A clearer picture of microbial biogeography.

Amich J*, Mokhtari Z*, Strobel M, Vialetto E, Sheta D, Yu Y, Hartweg J, Kalleda N, Jarick KJ, Brede C, Jordán-Garrote AL, Thusek S, Schmiedgen K, Arslan B, Pinnecker J, Thornton CR, Gunzer M, Krappmann S, Einsele H, Heinze KG, Beilhack A. (2020). 3D light sheet fluorescence microscopy of lungs to dissect local host immune – Aspergillus fumigatusinteractions. mBio 11(1): e02752-19

T cells induce interferon-dependent cell cycle regulator pathways in cancer cells as a key immune mechanism to control cancer

A new paper in Nature Communications by Brenner et al. demonstrates in mice and in human patients that cancer control strictly requires the activation of tumour-intrinsic, senescence-inducing cell cycle regulators by the immune system to stably arrest those cancer cells that escape from eradication.

Cancer immunosurveillance, cancer immune senescence-signalling, immunotherapy, Andreas Beilhack research laboratory, immunology program Würzburg university

Mechanisms of cancer immunosurveillance. (A) Conventional and cancer immunotherapies can enhance direct cytolytic effector mechanisms of cytotoxic T cells and NK cells. (B) TNF and interferon released by Th1 T cells can induce and maintain cancer cell senescence. Mutations in the interferon-senescence-signalling pathway in tumor metastases can abolish this important mechanism and result in cancer progression.

Recent advances in cancer immunotherapy allow to efficiently unleash immune effector cells. Consequently, T cells, NK cells and macrophages can kill malignant cells throughout the body in patients with hematologic and solid cancers. Even if these therapies primarily aim to completely eradicate all cancer cells, often enough cancer cell killing remains incomplete and does not sufficiently and permanently control cancer. Moreover, the majority of cancer-related deaths do not result from the primary tumor. Instead, months or even years after initial therapy, cancer metastases arise from reawakened, dormant cancer cells that had been resistant to chemo-, radiation- or immunotherapies.

In a collaborative multidisciplinary effort lead by the team of Prof. Dr. Martin Röcken from Tübingen University and scientists from Tübingen and Würzburg University, we uncovered that IFN-γ/STAT1-dependent activation of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf and p21Cip1 is required to keep cancer cells in a senescent state that had escaped immune cell mediated killing. Conversely, metastases that acquire mutations in the IFN-γ-senescence-inducing signalling pathways become resistant to immunotherapies and progress. In line with this, our study discovered that more than half of the metastases of patients not responding to immune checkpoint inhibitor therapy had at least one defect or genetic alterations in the IFN-dependent senescence-signalling pathway. Consequently, drugs that can re-invigorate the senescence-signalling pathways in cancer cells such as CDK4/6 inhibitors appear promising to be combined with cancer immunotherapy.

This work pinpointing key mechanisms required for protection against cancer cells that escape from cytotoxicity was supported by the German Research Council (Deutsche Forschungsgemeinschaft) in the research consortium FOR2314 Targeting therapeutic windows in essential cellular processes for tumor therapy and the Wilhelm Sander-Stiftung.

Optical lung scans of host-pathogen interactions

In a new publication that appeared today in the journal mBio we present light-sheet fluorescence microscopy that pinpoints critical immune cell populations responding to an invasive fungal lung infection.

Read more about our new research article on how a powerful microscopy technique helps scientists to find a needle in a haystack – only 2 micrometer thick fungal spores (50 times thinner than a hair) in an entire lung to learn about the ensuing immune response.

A gala event for cancer research

In an outstanding gala event, our joint research endeavor with the team of Prof. Harald Wajant was awarded to advance cancer immunotherapy.

Cancer research, immunotherapy, Andreas Beilhack laboratory, Würzburg Germany, Stiftung Forschung Hilft! Gabriele NelkenstockOn November 16, 2019, the foundation Forschung Hilft! invited to the new Hotel Melchior Park in Würzburg for a fabulous fund-raising gala evening “Art & Music & Magic.” At the same event, our research effort towards developing new concepts for cancer therapy was honored: The foundation “Forschung Hilft” selected our research project for its annual Großen Förderpreis worth 20.000 Euros. Receiving this award was a wonderful and highly motivating experience knowing that Ms. Gabriele Nelkenstock and her dedicated team of the foundation raised the funds for this cancer research award from patients and committed private donors.

The award will directly support one of our cutting-edge projects to reactivate the body’s immune response against cancer. We want to achieve this by newly designed antibody fusion proteins. The effect of these antibody fusion proteins only unfolds in the immediate vicinity of cancer cells, so that the body’s immune response is only activated there. The advantage of our therapy concept is that no immune cells need to be manipulated from the outside. Furthermore, disadvantages of previously clinically tested immune-activating antibodies can be minimized, such as side effect profiles or systemic effects.

The research groups of Prof. Andreas Beilhack and Prof. Harald Wajant have collaborated on the immune regulation of inflammatory diseases and cancer for more than 10 years. In this collaborations, they particularly focus on the molecular and cellular mechanisms of action of the tumor necrosis factor receptor superfamily. The molecular biological and biochemical expertise of Prof. Wajant’s group and the experience of Prof. Beilhack’s group in immunotherapy and cancer complement each other in an excellent way. The interdisciplinary team consists of experienced biologists, molecular biologists, biochemists, bioinformaticians, technical assistants and clinicians.

The Große Förderpreis of the Foundation “Forschung Hilft!” sets the first foundation stone to develop a new type of cancer therapy. Thank you!

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