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LAG3 Regulates T Cell Activation and Plaque Infiltration in Atherosclerotic Mice

Mulholland, Megan LU ; Kritikou, Eva ; Katra, Pernilla LU ; Nilsson, Jan LU ; Björkbacka, Harry LU orcid ; Lichtman, Andrew H. ; Rodriguez, Annabelle and Engelbertsen, Daniel LU (2022) In JACC: CardioOncology 4(5). p.635-645
Abstract

Background: 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. Objectives: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis. Methods: 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... (More)

Background: 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. Objectives: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis. Methods: 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. Results: 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. Conclusions: 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.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
atherosclerosis, cardiovascular disease, immune checkpoint blockade, inflammation, T cells
in
JACC: CardioOncology
volume
4
issue
5
pages
635 - 645
publisher
Elsevier
external identifiers
  • scopus:85143674333
  • pmid:36636446
ISSN
2666-0873
DOI
10.1016/j.jaccao.2022.09.005
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022 The Authors
id
43aeca2c-77a4-4f58-b94d-16e03b213870
date added to LUP
2022-12-28 11:25:28
date last changed
2024-09-20 07:35:29
@article{43aeca2c-77a4-4f58-b94d-16e03b213870,
  abstract     = {{<p>Background: 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. Objectives: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis. Methods: To study the role of LAG3 in atherosclerosis, we investigated both bone marrow chimeras lacking LAG3 in hematopoietic cells as well as global Lag3<sup>-/-</sup> 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<sup>-/-</sup>) mice and evaluated by histology and flow cytometry. Results: 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. Conclusions: 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.</p>}},
  author       = {{Mulholland, Megan and Kritikou, Eva and Katra, Pernilla and Nilsson, Jan and Björkbacka, Harry and Lichtman, Andrew H. and Rodriguez, Annabelle and Engelbertsen, Daniel}},
  issn         = {{2666-0873}},
  keywords     = {{atherosclerosis; cardiovascular disease; immune checkpoint blockade; inflammation; T cells}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{635--645}},
  publisher    = {{Elsevier}},
  series       = {{JACC: CardioOncology}},
  title        = {{LAG3 Regulates T Cell Activation and Plaque Infiltration in Atherosclerotic Mice}},
  url          = {{http://dx.doi.org/10.1016/j.jaccao.2022.09.005}},
  doi          = {{10.1016/j.jaccao.2022.09.005}},
  volume       = {{4}},
  year         = {{2022}},
}