Immune Checkpoint Inhibitor Therapy Aggravates T Cell-Driven Plaque Inflammation in Atherosclerosis.

Autor:	Poels K; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands., van Leent MMT; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Boutros C; Oncology Department, Institut de Cancérologie Gustave Roussy, Villejuif, France., Tissot H; Radiology Department, Institut de Cancérologie Gustave Roussy, Paris, France., Roy S; Oncology Department, Institut de Cancérologie Gustave Roussy, Villejuif, France., Meerwaldt AE; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Toner YCA; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Reiche ME; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands., Kusters PJH; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands., Malinova T; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands., Huveneers S; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands., Kaufman AE; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Mani V; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Fayad ZA; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., de Winther MPJ; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands., Marabelle A; Oncology Department, Institut de Cancérologie Gustave Roussy, Villejuif, France., Mulder WJM; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands., Robert C; Oncology Department, Institut de Cancérologie Gustave Roussy, Villejuif, France.; Faculty of Medicine, Universite Paris-Saclay, Le Kremlin-Bicêtre, France., Seijkens TTP; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.; Department of Hematology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Lutgens E; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.; Institute for Cardiovascular Prevention, Ludwig Maximilian University of Munich, Munich, Germany.; German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany.
Jazyk:	angličtina
Zdroj:	JACC. CardioOncology [JACC CardioOncol] 2020 Oct 06; Vol. 2 (4), pp. 599-610. Date of Electronic Publication: 2020 Oct 06 (Print Publication: 2020).
DOI:	10.1016/j.jaccao.2020.08.007
Abstrakt:	Background: Immunotherapy has revolutionized cancer treatment. However, immune checkpoint inhibitors (ICIs) that target PD-1 (programmed cell death protein-1) and/or CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) are commonly associated with acute immune-related adverse events. Accumulating evidence also suggests that ICIs aggravate existing inflammatory diseases. Objectives: As inflammation drives atherosclerotic cardiovascular disease, we studied the propensity of short-term ICI therapy to aggravate atherosclerosis. Methods: We used 18 F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) positron emission tomography-computed tomography to detect macrophage-driven vascular and systemic inflammation in pembrolizumab and nivolumab/ipilimumab-treated melanoma patients. In parallel, atherosclerotic Ldlr -/- mice were treated with CTLA-4 and PD-1 inhibition to study the proinflammatory consequences of immune checkpoint inhibition. Results: ICI treatment did not affect 18 F-FDG uptake in the large arteries, spleen, and bone marrow of melanoma patients, nor myeloid cell activation in blood and lymphoid organs in hyperlipidemic mice. In contrast, we found marked changes in the adaptive immune response (i.e., increased CD4 + effector T cell and CD8 + cytotoxic T cell numbers in lymphoid organs and the arterial wall of our hyperlipidemic mice). Although plaque size was unaffected, plaques had progressed toward a lymphoid-based inflammatory phenotype, characterized by a 2.7-fold increase of CD8 + T cells and a 3.9-fold increase in necrotic core size. Increased endothelial activation was observed with a 2.2-fold and 1.6-fold increase in vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, respectively. Conclusions: This study demonstrates that combination therapy with anti-CTLA-4 and anti-PD-1 antibodies does not affect myeloid-driven vascular and systemic inflammation in melanoma patients and hyperlipidemic mice. However, short-term ICI therapy in mice induces T cell-mediated plaque inflammation and drives plaque progression. Competing Interests: This study was supported by the Netherlands Heart Institute (Young@heart grant to Dr. Seijkens), the Dutch Heart Foundation (Dr. Dekker Physician-in-specialty-training grant to Dr. Seijkens), the Netherlands Organization for Scientific Research (VICI grant 016.130.676 to Dr. Lutgens, VICI grant 91818622 to Dr. Mulder), the European Union (H2020-PHC-2015-667673, REPROGRAM to Dr. Lutgens), the European Research Council (ERC consolidator grant CD40-INN 681492 to Dr. Lutgens), and the German Science Foundation (CRC1123, project A5 to Dr. Lutgens). This work was also supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences for the GENIUS-II project “Generating the best evidence-based pharmaceutical targets for atherosclerosis,” the National Institutes of Health (grants R01 CA220234, R01 HL144072, and P01 HL131478 to Dr. Mulder), and the American Heart Association (grant 19PRE34380423 to Dr. van Leent). Dr. Marabelle has served on scientific advisory boards and provided consulting services for Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, AstraZeneca, Sanofi, and Roche. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Databáze:	MEDLINE
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