Abstract
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 18F-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 18F-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.
Original language | English |
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Pages (from-to) | 599-610 |
Number of pages | 12 |
Journal | JACC: CardioOncology |
Volume | 2 |
Issue number | 4 |
DOIs | |
Publication status | Published - Nov 2020 |
Funding
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. The authors thank Myrthe den Toom and Linda Beckers for technical support.
Funders | Funder number |
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Dutch Heart Foundation | |
Koninklijke Nederlandse Akademie van Wetenschappen | |
National Institutes of Health | P01 HL131478, R01 CA220234, R01 HL144072 |
American Heart Association | 19PRE34380423 |
European Union's Horizon 2020 - Research and Innovation Framework Programme | 681493 |
European Commission | H2020-PHC-2015-667673 |
H2020 European Research Council | CD40-INN 681492 |
Deutsche Forschungsgemeinschaft | CRC1123 |
ZonMw : Dutch Organisation for Health Research and Development | |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 016.130.676, 91818622 |
Netherlands Heart Institute |
Keywords
- atherosclerosis
- CTLA4
- immune checkpoint inhibitors
- inflammation
- PD-1