Dissecting the anti-tumour effector functions of trained neutrophils

Tumours hijack neutrophils, which in turn adopt an immunosuppressive and tumour-promoting phenotype. Induction of trained immunity with β-glucan can reverse this hijacking and promotes generation of neutrophils with potent anti-tumour activity, as we have shown in our previous work and our preliminary data from the first funding period. Trained tumour-associated neutrophils (TANs) exert their tumouricidal activity via production of reactive oxygen species (ROS). Moreover, trained TANs display a unique signature, including downregulation of CD44 alongside metabolic changes and upregulation of the necroptosis and inflammatory signalling regulator Receptor Interacting Serine/Threonine Kinase 3 (RIPK3) as well as of anti-ferroptosis systems. These data suggest that metabolic rewiring of trained TANs may underlie their anti-tumour functions. We therefore perform a detailed characterization of the phenotype and especially metabolism of trained TANs, define the role of RIPK3-dependent signalling pathway for mediating the ROS-producing trained TAN phenotype and thoroughly understand the role of anti-ferroptosis mechanisms for the survival and anti-tumour function of trained TANs within the ROS-rich tumour microenvironment.

Chavakis
Triantafyllos, MD

TUD

Institute for Clinical Chemistry and Laboratory Medicine

Team

Kalafati
Lydia, PhD

TUD

Sidiropoulos
Panagiotis, PhD student

TUD

Publications

A1 A2 A3 A5 B3 B4 C5 Z1 Divergent Granulopoiesis at Extramedullary Sites Safeguards Antibacterial Host Defense Silvestre-Roig, C.; Chevre, R.; Farjia, M.; Bender, A.; Vöcking, L. M.; Richter, M.; Hageb, A.; Suerdieck, V.; Arenas Cerro, F. J.; Braster, Q.; Guzman, M.; Sintes, J.; Sharma, S.; Lemnitzer, P.; Tulotta, C.; Börgeling, Y.; Herrero-Cervera, A.; Flueter, H.; Reinartz Groba, S. N.; Ahern, D.; Osei-Sarpong, C.; Zimmer, R.; Alonso-Gonzalez, N.; Ortega, E.; Lienenklaus, S.; Kalinke, U.; Ludwig, S.; Engel, D. R.; Rosenbauer, F.; Monaco, C.; Dersch, P.; Kibler, A.; Cerutti, A.; Chavakis, T.; Benedito, R.; Hidalgo, A.; Jablonska, J.; Palomino-Segura, M.; Soehnlein, O. 2026 Sci Immunol https://doi.org/10.1126/sciimmunol.adw7077
B4 Bone Marrow Rewired: Trained Immunity and Clonal Hematopoiesis in Metabolic Disease Chronopoulos, J.; Hajishengallis, G.; Chavakis, T. 2026 Metabolism https://doi.org/10.1016/j.metabol.2026.156603
B4 Inflammageing and Clonal Haematopoiesis Interplay and Their Impact on Human Disease Hajishengallis, G.; Chavakis, T. 2026 Nat Rev Mol Cell Biol https://doi.org/10.1038/s41580-025-00936-y
A2 A3 B4 B6 C5 C6 Z1 TSP1/TGF-Β1 Drives Arachidonic Acid Metabolism to Orchestrate Neutrophil Swarming Widera, L.; Spangenberg, P.; Siemes, D.; Bessler, S.; Bottek, J.; Voss, H.; Novak, A.; Hueser, D.; Richter, M.; Potthoff, A.; Siebels, B.; Moritz, M.; Gocke, A.; Thiebes, S.; Tautges, S.; Chavakis, T.; Jablonska, J.; Lämmermann, T.; Gunzer, M.; Schlüter, H.; Hahn, J.; Grüneboom, A.; Soehnlein, O.; Dreisewerd, K.; Soltwisch, J.; Shevchuk, O.; Engel, D. R. 2025 bioRxiv https://doi.org/10.1101/2025.11.25.688397
B4 Trained Immunity in Cardiovascular Disease Riksen, N. P.; Netea, M. G.; Ait-Oufella, H.; Chavakis, T.; Hajishengallis, G. 2025 Eur Heart J https://doi.org/10.1093/eurheartj/ehaf982
B4 Central Trained Immunity in the Context of Bladder Cancer Immunotherapy Chronopoulos, J.; Crespo, M.; Chavakis, T. 2025 Cancer Cell https://doi.org/10.1016/j.ccell.2025.06.010
B4 Innate Immune Training of Osteoclastogenesis Promotes Inflammatory Bone Loss in Mice Haacke, N.; Wang, H.; Yan, S.; Barovic, M.; Li, X.; Nagai, K.; Botezatu, A.; Hatzioannou, A.; Gercken, B.; Trimaglio, G.; Shah, A. U.; Wang, J.; Ye, L.; Jaykar, M. T.; Rauner, M.; Wielockx, B.; Chung, K.-J.; Netea, M. G.; Kalafati, L.; Hajishengallis, G.; Chavakis, T. 2025 Dev Cell https://doi.org/10.1016/j.devcel.2025.02.001
B4 Trained Immunity in Chronic Inflammatory Diseases and Cancer. Hajishengallis, G.; Netea, M. G.; Chavakis, T. 2025 Nat Rev Immunol https://doi.org/10.1038/s41577-025-01132-x
A2 B4 Z1 Formyl Peptide Receptor 2 (FPR2) Regulates Dendritic Cell Metabolism and Th17 Cell Differentiation during Neuroinflammation Lim, J.-H.; Neuwirth, A.; Chung, K.-J.; Grossklaus, S.; Soehnlein, O.; Hajishengallis, G.; Chavakis, T. 2024 Front Immunol
B4 Central Trained Immunity and Its Impact on Chronic Inflammatory and Autoimmune Diseases Hajishengallis, G.; Chavakis, T. 2024 J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2024.06.005
B4 Clonal Hematopoiesis Driven by Mutated DNMT3A Promotes Inflammatory Bone Loss Wang, H.; Divaris, K.; Pan, B.; Li, X.; Lim, J.-H.; Saha, G.; Barovic, M.; Giannakou, D.; Korostoff, J. M.; Bing, Y.; Sen, S.; Moss, K.; Wu, D.; Beck, J. D.; Ballantyne, C. M.; Natarajan, P.; North, K. E.; Netea, M. G.; Chavakis, T.; Hajishengallis, G. 2024 Cell https://doi.org/10.1016/j.cell.2024.05.003
A1 B4 Novel Possibilities for Targeting Neutrophils in Cancer Silvestre-Roig, C.; Kalafati, L.; Chavakis, T. 2024 Sig Transduct Target Ther https://doi.org/10.1038/s41392-024-01786-4
B4 Potent induction of trained immunity by Saccharomyces cerevisiae β-glucans Vuscan, P.; Kischkel, B.; Hatzioannou, A.; Markaki, E.; Sarlea, A.; Tintoré, M.; Cuñé, J.; Verginis, P.; de Lecea, C.; Chavakis, T.; Joosten, L. A. B.; Netea, M. G. 2024 Front Immunol https://doi.org/10.3389/fimmu.2024.1323333
B4 CD38 promotes hematopoietic stem cell dormancy Ibneeva, L.; Singh, S. P.; Sinha, A.; Eski, S. E.; Wehner, R.; Rupp, L.; Kovtun, I.; Pérez-Valencia, J. A.; Gerbaulet, A.; Reinhardt, S.; Wobus, M.; von Bonin, M.; Sancho, J.; Lund, F.; Dahl, A.; Schmitz, M.; Bornhäuser, M.; Chavakis, T.; Wielockx, B.; Grinenko, T. 2024 PLoS Biol https://doi.org/10.1371/journal.pbio.3002517
B4 An IL-10/DEL-1 Axis Supports Granulopoiesis and Survival from Sepsis in Early Life Vergadi, E.; Kolliniati, O.; Lapi, I.; Ieronymaki, E.; Lyroni, K.; Alexaki, V. I.; Diamantaki, E.; Vaporidi, K.; Hatzidaki, E.; Papadaki, H. A.; Galanakis, E.; Hajishengallis, G.; Chavakis, T.; Tsatsanis, C. 2024 Nat Commun https://doi.org/10.1038/s41467-023-44178-y
B4 A Novel Macrolide-Del-1 Axis to Regenerate Bone in Old Age Sirisereephap, K.; Tamura, H.; Lim, J.-H.; Surboyo, M. D. C.; Isono, T.; Hiyoshi, T.; Rosenkranz, A. L.; Sato-Yamada, Y.; Domon, H.; Ikeda, A.; Hirose, T.; Sunazuka, T.; Yoshiba, N.; Okada, H.; Terao, Y.; Maeda, T.; Tabeta, K.; Chavakis, T.; Hajishengallis, G.; Maekawa, T. 2024 iScience https://doi.org/10.1016/j.isci.2024.108798.
B4 Macrophage Function in Adipose Tissue Homeostasis and Metabolic Inflammation Chavakis, T.; Alexaki, V. I.; Ferrante, A. W. 2023 Nat Immunol https://doi.org/10.1038/s41590-023-01479-0
B4 The Role of Neutrophils in Trained Immunity Kalafati, L.; Hatzioannou, A.; Hajishengallis, G.; Chavakis, T. 2022 Immunol Rev https://doi.org/10.1111/imr.13142
B4 Mechanisms and Therapeutic Modulation of Neutrophil-Mediated Inflammation Hajishengallis, G.; Chavakis, T. 2022 J Dent Res https://doi.org/10.1177/00220345221107602