Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma
Abstract
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.
Article Details
Authors (47)
Adrian Gottschlich
Ludwig Maximilian University Hospital, Munich, Germany
Ruth Grünmeier
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Gordon Victor Hoffmann
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Sayantan Nandi
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Vladyslav Kavaka
5Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
Philipp Jie Müller
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Jakob Jobst
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Arman Oner
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Rainer Kaiser
Ludwig Maximilian University Hospital, Munich, Germany
Jan Gärtig
Ignazio Piseddu
Stephanie Frenz-Wiessner
1Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
Savannah D. Fairley
11Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Heiko Schulz
14Institute of Pathology, Faculty of Medicine, Ludwig Maximilian University Munich, Munich, Germany
Veronika Igl
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Thomas Alexander Janert
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Lea Di Fina
8Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany
Maité Mulkers
1University Hospital of Ludwig Maximilian University
Moritz Thomas
15Institute of AI for Health, Helmholtz Zentrum München-German Research Center for Environmental Health Neuherberg, Neuherberg, Germany
Daria Briukhovetska
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Donjetë Simnica
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Emanuele Carlini
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Christina Angeliki Tsiverioti
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Marcel P. Trefny
Theo Lorenzini
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Florian Märkl
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Pedro Mesquita
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Ruben Brabenec
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Thaddäus Strzalkowski
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Sophia Stock
1LMU University Hospital, Department of Medicine III, Munich, Germany
Stefanos Michaelides
2Division of Clinical Pharmacology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Member of the German Center for Lung Research, Munich, Germany
Johannes Hellmuth
16University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
Martin Thelen
8Faculty of Medicine and University Hospital Cologne, University of Cologne, Department of Nuclear Medicine, Cologne, Germany
Sarah Reinke
3University Hospital Schleswig-Holstein, Campus Kiel, Department of Pathology, Hematopathology Section and Lymph Node Registry, Kiel, Germany
Wolfram Klapper
Pascal Francois Gelebart
20Department of Clinical Science, University of Bergen, Bergen, Norway
Leo Nicolai
1Medizinische Klinik und Poliklinik I, University Hospital Ludwig Maximilian University, Munich, Germany
Carsten Marr
Eduardo Beltrán
Remco T. A. Megens
Christoph Klein
Fraunhofer Institute for Solar Energy Systems ISE, Division Photovoltaics 1 , Heidenhofstr. 2, 79110 Freiburg,
Fanny Baran-Marszak
6Département de recherche Clinique, Hôpital Avicenne, APHP, Bobigny, France
Andreas Rosenwald
Michael von Bergwelt-Baildon
Ludwig Maximilian University Hospital, Munich, Germany
Paul J. Bröckelmann
Stefan Endres
Sebastian Kobold