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
N1 - Publisher Copyright:
© 2020
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 - CTLA4
KW - PD-1
KW - atherosclerosis
KW - immune checkpoint inhibitors
KW - inflammation
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
AN - SCOPUS:85095417686
SN - 2666-0873
VL - 2
SP - 599
EP - 610
JO - JACC: CardioOncology
JF - JACC: CardioOncology
IS - 4
ER -