Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma

The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell-based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86-CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.

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Publication Details

Journal
Blood
Published
2025-04-03
DOI
https://doi.org/10.1182/blood.2023022197
Citations
8
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
7.32

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article

Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma

Martin Thelen, Ignazio Piseddu, Sophia Stock, Florian Märkl et al.
8 citations
Blood
CAR-T cell therapy research
7.32
article

Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma

Martin Thelen, Ignazio Piseddu, Sophia Stock, Florian Märkl, Fanny Baran‐Marszak, Michael von Bergwelt‐Baildon, Arman Öner, Rainer Kaiser, Donjetë Simnica, Adrian Gottschlich, Sarah Reinke, Philipp Jie Müller, Stefan Endres, Jan Gärtig, Emanuele Carlini, Sayantan Nandi, Carsten Marr, Gordon Victor Hoffmann, Andreas Rosenwald, Moritz Thomas, Remco T. A. Megens, Stephanie Frenz-Wiessner, Sebastian Kobold, Veronika Igl, Theo Lorenzini, Paul J. Bröckelmann, Stefanos Michaelides, Heiko Schulz, Johannes C. Hellmuth, Marcel P. Trefny, Christina Angeliki Tsiverioti, Pascal Gélébart, Savannah Fairley, Ruth Grünmeier, Leo Nicolai, Ruben Brabenec, Eduardo Beltrán, Daria Briukhovetska, Vladyslav Kavaka, Thaddäus Strzalkowski, Jakob Jobst, Christoph Klein, Wolfram Klapper, Lea Di Fina, Maité Mulkers, Thomas Alexander Janert, Pedro Mesquita
article en
8 citations

Abstract

The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell-based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86-CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.

BloodVol. 145(14)
Inserm (FR), German Cancer Research Center (DE), University of Cologne (DE), Heidelberg University (DE), University of Würzburg (DE), Maastricht University Medical Centre (NL), Haukeland University Hospital (NO), University Hospital Heidelberg (DE), Visma (Norway) (NO), Helmholtz Zentrum München (DE), LMU Klinikum (DE), BG Klinik Tübingen (DE), Sorbonne Université (FR), German Center for Pediatric and Adolescent Rheumatology (DE), Düsseldorf University Hospital (DE), Université Sorbonne Paris Nord (FR), Institute for Sports Medicine (DE), Comprehensive Cancer Center Mainfranken (DE), University Hospital Schleswig-Holstein (DE), Munich Cluster for Systems Neurology (DE), Universitätsklinikum Würzburg (DE), German Centre for Cardiovascular Research (DE), Hôpital Avicenne (FR), German Center for Lung Research (DE), University Hospital Cologne (DE), Max Planck Institute for Biology of Ageing (DE), Heinrich Heine University Düsseldorf (DE), University of Bergen (NO), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE), University of Lübeck (DE)
Melanoma Research Alliance, Novartis Foundation, Wilhelm Sander-Stiftung, Fritz-Bender-Stiftung, European Commission, Deutsche Forschungsgemeinschaft, Volkswagen Foundation, Bundesministerium für Bildung und Forschung, Bayerische Forschungsstiftung, Else Kröner-Fresenius-Stiftung, José Carreras Leukämie-Stiftung, Ludwig-Maximilians-Universität München, Deutsche Krebshilfe, Institut National Du Cancer, Deutschen Konsortium für Translationale Krebsforschung, Hector Stiftung, Elitenetzwerk Bayern, Eurostars
Good health and well-being
Openalex Percentile: Top 3%
CAR-T cell therapy research
7.32
DOIOpen Access PDFOpenAlex
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