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

Kikkie Poels; Mandy M.T. van Leent; Celine Boutros; Hubert Tissot; Séverine Roy; Anu E. Meerwaldt; Yohana C.A. Toner; Myrthe E. Reiche; Pascal J.H. Kusters; Tsveta Malinova; Stephan Huveneers; Audrey E. Kaufman; Venkatesh Mani; Zahi A. Fayad; Menno P.J. de Winther; Aurelien Marabelle; Willem J.M. Mulder; Caroline Robert; Tom T.P. Seijkens; Esther Lutgens

doi:10.1016/j.jaccao.2020.08.007

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

Kikkie Poels, Mandy M.T. van Leent, Celine Boutros, Hubert Tissot, Séverine Roy, Anu E. Meerwaldt, Yohana C.A. Toner, Myrthe E. Reiche, Pascal J.H. Kusters, Tsveta Malinova, Stephan Huveneers, Audrey E. Kaufman, Venkatesh Mani, Zahi A. Fayad, Menno P.J. de Winther, Aurelien Marabelle, Willem J.M. Mulder, Caroline Robert, Tom T.P. Seijkens, Esther Lutgens (Corresponding author)

Research output: Contribution to journal › Article › Academic › peer-review

104 Citations (Scopus)

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
Pages (from-to)	599-610
Number of pages	12
Journal	JACC: CardioOncology
Volume	2
Issue number	4
DOIs	https://doi.org/10.1016/j.jaccao.2020.08.007
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
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaccao.2020.08.007

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Poels, K., van Leent, M. M. T., Boutros, C., Tissot, H., Roy, S., Meerwaldt, A. E., Toner, Y. C. A., Reiche, M. E., Kusters, P. J. H., Malinova, T., Huveneers, S., Kaufman, A. E., Mani, V., Fayad, Z. A., de Winther, M. P. J., Marabelle, A., Mulder, W. J. M., Robert, C., Seijkens, T. T. P., & Lutgens, E. (2020). Immune Checkpoint Inhibitor Therapy Aggravates T Cell–Driven Plaque Inflammation in Atherosclerosis. JACC: CardioOncology, 2(4), 599-610. https://doi.org/10.1016/j.jaccao.2020.08.007

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title = "Immune Checkpoint Inhibitor Therapy Aggravates T Cell–Driven Plaque Inflammation in Atherosclerosis",

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.",

keywords = "atherosclerosis, CTLA4, immune checkpoint inhibitors, inflammation, PD-1",

author = "Kikkie Poels and {van Leent}, {Mandy M.T.} and Celine Boutros and Hubert Tissot and S{\'e}verine Roy and Meerwaldt, {Anu E.} and Toner, {Yohana C.A.} and Reiche, {Myrthe E.} and Kusters, {Pascal J.H.} and Tsveta Malinova and Stephan Huveneers and Kaufman, {Audrey E.} and Venkatesh Mani and Fayad, {Zahi A.} and {de Winther}, {Menno P.J.} and Aurelien Marabelle and Mulder, {Willem J.M.} and Caroline Robert and Seijkens, {Tom T.P.} and Esther Lutgens",

year = "2020",

month = nov,

doi = "10.1016/j.jaccao.2020.08.007",

language = "English",

volume = "2",

pages = "599--610",

journal = "JACC: CardioOncology",

issn = "2666-0873",

publisher = "Elsevier",

number = "4",

}

Poels, K, van Leent, MMT, Boutros, C, Tissot, H, Roy, S, Meerwaldt, AE, Toner, YCA, Reiche, ME, Kusters, PJH, Malinova, T, Huveneers, S, Kaufman, AE, Mani, V, Fayad, ZA, de Winther, MPJ, Marabelle, A, Mulder, WJM, Robert, C, Seijkens, TTP & Lutgens, E 2020, 'Immune Checkpoint Inhibitor Therapy Aggravates T Cell–Driven Plaque Inflammation in Atherosclerosis', JACC: CardioOncology, vol. 2, no. 4, pp. 599-610. https://doi.org/10.1016/j.jaccao.2020.08.007

TY - JOUR

T1 - Immune Checkpoint Inhibitor Therapy Aggravates T Cell–Driven Plaque Inflammation in Atherosclerosis

AU - Poels, Kikkie

AU - van Leent, Mandy M.T.

AU - Boutros, Celine

AU - Tissot, Hubert

AU - Roy, Séverine

AU - Meerwaldt, Anu E.

AU - Toner, Yohana C.A.

AU - Reiche, Myrthe E.

AU - Kusters, Pascal J.H.

AU - Malinova, Tsveta

AU - Huveneers, Stephan

AU - Kaufman, Audrey E.

AU - Mani, Venkatesh

AU - Fayad, Zahi A.

AU - de Winther, Menno P.J.

AU - Marabelle, Aurelien

AU - Mulder, Willem J.M.

AU - Robert, Caroline

AU - Seijkens, Tom T.P.

AU - Lutgens, Esther

PY - 2020/11

Y1 - 2020/11

N2 - 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.

AB - 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.

KW - atherosclerosis

KW - CTLA4

KW - immune checkpoint inhibitors

KW - inflammation

KW - PD-1

UR - http://www.scopus.com/inward/record.url?scp=85095417686&partnerID=8YFLogxK

U2 - 10.1016/j.jaccao.2020.08.007

DO - 10.1016/j.jaccao.2020.08.007

M3 - Article

C2 - 34396271

AN - SCOPUS:85095417686

SN - 2666-0873

VL - 2

SP - 599

EP - 610

JO - JACC: CardioOncology

JF - JACC: CardioOncology

IS - 4

ER -

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

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Keywords

UN SDGs

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