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Jan Nilsson

Professor

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LAG3 Regulates T Cell Activation and Plaque Infiltration in Atherosclerotic Mice

Author

  • Megan Mulholland
  • Eva Kritikou
  • Pernilla Katra
  • Jan Nilsson
  • Harry Björkbacka
  • Andrew H. Lichtman
  • Annabelle Rodriguez
  • Daniel Engelbertsen

Summary, in English

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.

Department/s

  • Cardiovascular Research - Cellular Metabolism and Inflammation
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Cardiovascular Research - Immunity and Atherosclerosis
  • EpiHealth: Epidemiology for Health
  • Cardiovascular Research - Matrix and Inflammation in Atherosclerosis

Publishing year

2022-12

Language

English

Pages

635-645

Publication/Series

JACC: CardioOncology

Volume

4

Issue

5

Document type

Journal article

Publisher

Elsevier

Topic

  • Immunology

Keywords

  • atherosclerosis
  • cardiovascular disease
  • immune checkpoint blockade
  • inflammation
  • T cells

Status

Published

Research group

  • Cardiovascular Research - Cellular Metabolism and Inflammation
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Cardiovascular Research - Matrix and Inflammation in Atherosclerosis

ISBN/ISSN/Other

  • ISSN: 2666-0873