Professor Dr Sascha Dietrich (Director of the Department of Hematology, Oncology and Clinical Immunology) emphasises that the targeted modulation of stromal cells offers great therapeutic potential for the treatment of malignant lymphomas.
Photo Credit: © UKD
Scientific Frontline: Extended "At a Glance" Summary: The Influence of Lymph Node Architecture on Lymphoma
The Core Concept: Stromal cells function as the "architects" of lymph nodes by directing immune cells via chemical signals, but during the development of B cell lymphomas, inflammatory feedback loops reprogram these cells, actively destroying the lymph node's structural organization.
Key Distinction/Mechanism: Unlike the passive displacement of tissue by tumor growth, the structural breakdown in aggressive lymphomas (such as diffuse large B cell lymphoma) is an active process. T cell-produced interferons force stromal cells to replace structure-defining chemokines with inflammatory ones, attracting more inflammatory cells and obliterating the spatial boundaries that remain largely intact in slower-growing lymphomas (such as follicular lymphoma).
Major Frameworks/Components:
- Stromal Cell Regulation: Non-haematopoietic structural cells that normally release chemokines to organize B cells and T cells into specific zones.
- Inflammatory Feedback Loop: The active mechanism where T cells produce interferons in the tumor microenvironment, fundamentally altering stromal chemokine production.
- Advanced Tissue Mapping: The utilization of single-cell analyses and spatial tissue mapping to trace the progressive loss of regulatory signals.
Branch of Science: Oncology, Hematology, and Clinical Immunology.
Future Application: The targeted modulation of inflammatory signals and the stabilization of stromal cells offer promising new therapeutic approaches for treating malignant lymphomas. Furthermore, specific chemokine profiles could serve as novel biomarkers for the early identification of aggressive disease progression.
Why It Matters: The reprogramming of stromal cells and the resulting loss of tissue organization directly correlate with highly unfavorable prognoses and poorer patient survival rates. Understanding this active breakdown process shifts clinical focus toward the tumor microenvironment as a critical target for improving lymphoma outcomes.
Researchers at Heinrich Heine University Düsseldorf (HHU) and University Hospital Düsseldorf (UKD) have succeeded in mapping the organization of immune cells in human lymph nodes for the first time. The study was conducted in collaboration with the German Cancer Research Centre (DKFZ), the European Molecular Biology Laboratory (EMBL) in Heidelberg, the Berlin Institute of Health (BIH) at the Charité hospital Berlin and the University of Basel. They were able to show why lymph node architecture is progressively broken down in the case of malignant lymphomas. The researchers, led by Professor Dr Sascha Dietrich (UKD), have now published the results in the scientific journal Nature Cancer.
Lymph nodes are key control centers in the immune system and play an important role in defending the body against infections and tumors. For these processes to function properly, immune cells (B cells and T cells) must be organized in a precise spatial pattern in the lymph node tissue, for example in so-called B cell follicles and T cell zones. They are controlled by stromal cells (non-hematopoietic structural cells): They release messenger substances called chemokines, creating signals to guide the immune cells to their designated positions in the lymph node. In the case of B cell lymphomas, the internal structure of the lymph node tissue can be disturbed in very different ways, depending on the exact type of lymphoma: While the fundamental tissue structure remains intact in the case of slow-growing lymphomas such as follicular lymphoma (FL), aggressive lymphomas such as diffuse large B cell lymphoma (DLBCL) cause the tissue structure to break down completely. Why these typical growth patterns develop have been largely unclear to date.
In the study “Reprogramming of stroma-derived chemokine networks drives the loss of tissue organization in nodal B cell lymphoma”, the researchers coordinated by Professor Dietrich (Director of the Department of Hematology, Oncology and Clinical Immunology, UKD) have now succeeded in systematically mapping these processes in the human lymph node for the first time. By means of single-cell analyses and spatial tissue mapping, they were able to trace which factors lead to the progressive breakdown of the lymph node architecture in the case of lymphoma.
The data show: Stromal cells are the “architects” of the lymph node. The researchers were able to prove that central chemokine guiding signals in specialized stromal cells undergo fundamental changes over the course of lymphomagenesis, causing the progressive breakdown of the spatial structure of the lymph node. These stromal cell changes are reflected in the growth patterns of lymphomas – while there is a shift in the proportions of B cell follicles and T cell zones in FL, the areas remain spatially demarcated to a large extent; by contrast, there is widespread loss of important regulatory signals and thus tissue structure in DLBCL.
The study identified an inflammatory feedback loop as the driving mechanism: As part of the immune response in the tumor microenvironment, T cells produce inflammatory signaling proteins called interferons, which cause stromal cells to reprogram their chemokine production: instead of structure-defining signals, inflammatory chemokines dominate, which in turn attract further inflammatory cells. The loss of lymph node organization in lymphoma is thus not a passive effect of tumor growth, but rather actively driven by inflammation processes in the tumor microenvironment.
This reprogramming of stromal cells results in poorer patient survival rates. The study was able to demonstrate in large cohorts that a loss of structure-defining chemokines correlates with an unfavorable prognosis.
However, the findings also offer potential for new therapy approaches. “The study results show us that stabilization of the stromal cells or targeted modulation of the inflammatory signals could be a promising new therapy approach,” says Professor Dietrich. “The findings could also help us identify new biomarkers in the future to enable early identification of aggressive disease progression,” he concludes.
Additional information: The study took place within the framework of national and international collaboration. In addition to Professor Dietrich and the Department of Hematology, Oncology and Clinical Immunology at UKD, leading partners included Dr Felix Czernilofsky (University Hospital Heidelberg), Dr Anna Mathioudaki (EMBL), Dr Lea Jopp-Saile (Max Delbrück Center for Molecular Medicine, Berlin), Professor Dr Simon Haas (BIH, Max Delbrück Center for Molecular Medicine, Berlin, Queen Mary University of London), Dr Daniel Hübschmann (DKFZ) and Professor Dr Judith Zaugg (EMBL and the University of Basel).
In Düsseldorf, Christina Schniederjohann (MSc), Dr Nora Liebers, Dr Peter-Martin Bruch, PD Dr Marc Seifert (all from the Department of Hematology, Oncology and Clinical Immunology) and Professor Dr Jörg Distler (Department of Rheumatology) were also involved.
Published in journal: Nature Cancer
Authors: Felix Czernilofsky, Anna Mathioudaki, Lea Jopp-Saile, Raphael Lutz, Dominik Vonficht, Xi Wang, Christina Schniederjohann, Harald Voehringer, Tobias Roider, Marc-Andrea Baertsch, Claus Rodemer, Henry Löffler-Wirth, Michael Grau, Donnacha Fitzgerald, Johannes Mammen, Jan Kosla, Nora Liebers, Peter-Martin Bruch, Diana Ordoñez-Rueda, Alexander Brobeil, Gunhild Mechtersheimer, Caroline Pabst, Carsten Müller-Tidow, Andreas Trumpp, Marc Seifert, Frank Neumann, Mathias Heikenwälder, Vladimir Benes, Wolfgang Huber, Jörg Distler, Georg Lenz, Hans Binder, Reiner Siebert, Garry P. Nolan, Moritz Gerstung, Judith B. Zaugg, Daniel Hübschmann, Simon Haas, and Sascha Dietrich
Source/Credit: Heinrich Heine University Düsseldorf | Anne Wansing
Reference Number: ongy032626_01