%0 Journal Article
%T LAG3 Regulates T Cell Activation and Plaque Infiltration in Atherosclerotic Mice.
%A Mulholland M
%A Kritikou E
%A Katra P
%A Nilsson J
%A Björkbacka H
%A Lichtman AH
%A Rodriguez A
%A Engelbertsen D
%J JACC CardioOncol
%V 4
%N 5
%D Dec 2022
%M 36636446
%F 8.422
%R 10.1016/j.jaccao.2022.09.005
%X UNASSIGNED: The immune checkpoint receptor lymphocyte-activation gene 3 (LAG3) is a new target for immune checkpoint blockade (ICB), but the effects of LAG3 on atherosclerosis are not known.
UNASSIGNED: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis.
UNASSIGNED: To study the role of LAG3 in atherosclerosis, we investigated both bone marrow chimeras lacking LAG3 in hematopoietic cells as well as global Lag3 -/- knockout mice. Effects of anti-LAG3 monoclonal antibody monotherapy and combination therapy with anti-programmed cell death protein 1 (PD-1) were tested in hypercholesterolemic low-density lipoprotein receptor knockout (Ldlr -/- ) mice and evaluated by histology and flow cytometry.
UNASSIGNED: LAG3-deficiency or treatment with blocking anti-LAG3 monoclonal antibodies led to increased levels of both interferon gamma-producing T helper 1 cells and effector/memory T cells, balanced by increased levels of regulatory T cells. Plaque size was affected by neither LAG3 deficiency nor LAG3 blockade, although density of T cells in plaques was 2-fold increased by loss of LAG3. Combination therapy of anti-PD-1 and anti-LAG3 had an additive effect on T cell activation and cytokine production and promoted plaque infiltration of T cells.
UNASSIGNED: Loss of LAG3 function promoted T cell activation and accumulation in plaques while not affecting plaque burden. Our report supports further clinical studies investigating cardiovascular risk in patients treated with anti-LAG3 ICB.