The immune checkpoint molecule lymphocyte activation gene-3 (LAG3) may be important for regulating T-lymphocyte activation and inflammation in atherosclerotic plaques associated with atherosclerosis, according to findings from a study published in JACC: CardioOncology. Findings further suggest that treatment with anti-LAG3 monoclonal antibodies (mAbs) may promote vascular inflammation and atherosclerosis, having important implications for patients with certain forms of cancer who receive immune checkpoint blockade (ICB) therapy.
Researchers noted that LAG3 represents a newer target for ICB in cancer. Despite the promise of this approach for cancer treatment, the authors indicated little is known regarding the role of LAG3 in regulating inflammation within the cardiovascular system.
“As a general rule of thumb, treatments that boost immune responses against the tumor also promote the growth and inflammation of atherosclerotic plaques,” explained study author Daniel Engelbertsen, PhD, of Lund University in Sweden. “Likewise, treatments that have been efficient in pre-clinical models of atherosclerosis, such as boosting anti-inflammatory regulatory T cells, are associated with cancer.”
To further understand the role of LAG3 on plaque inflammation, researchers evaluated bone marrow chimeras that lacked LAG3 in hematopoietic cells as well as in global LAG3-/- knockout mice. The investigators tested the effects of anti-LAG3 mAbs, both alone and in combination with anti-programmed cell death protein 1 (PD1) therapy, in hypercholesterolemic low-density lipoprotein receptor knockout mice. Assessments were conducted by histology and flow cytometry.
A deficiency in LAG3 or treatment with blocking anti-LAG3 mAbs was associated with increased interferon gamma (IFN-g)–producing T-helper 1 cells as well as effector/memory T cells, with increased levels corresponding with increased regulatory T-cell levels. Although plaque size or burden was not affected by LAG3 deficiency or blockade, the researchers observed a two-fold increase in the density of T cells in plaques associated with the loss of LAG3.
Additionally, the combination of anti-LAG3 mAb and anti-PD1 therapy promoted the expansion of CD44hiCD62L- T-effector cells and IFN-g production of CD4þ and CD8þ T cells, with an additive effect observed with the combination treatment. Furthermore, the combination of anti-LAG3/anti-PD1 therapy increased the accumulation of lesional and adventitial CD4þ T cells, and levels of regulatory T cells expanded with the anti-PD1/anti-LAG3 combination treatment.
The investigators noted there may be functionality differences between the anti-LAG3 antibody used in the study and the approved human LAG3-targeting antibodies used in clinical practice.
Also, the researchers wrote that the ages of the mice used in the study could “have affected the impact of LAG3 blockade, as expression of markers of exhaustion are known to increase in aged mice.” The researchers added further research is needed to see whether ICB cessation would reverse plaque inflammation.
According to Dr. Engelbertsen, the findings support additional study and monitoring of cardiovascular complications in patients receiving anti-LAG3/anti-PD1 combination therapy for the management of advanced melanoma.
“Cardiovascular complications arising from immunotherapy will likely be a growing future concern due to the increase in patients receiving ICB,” Dr. Engelbertsen said. “Our study highlights the need for biomarkers to identify patients at risk of cardiovascular complications after ICB treatment and for translational studies aimed at the development of cardioprotective therapies tailored for patients receiving cancer immunotherapy.”
Corresponding author Annabelle Rodriguez, MD, of the University of Connecticut Health in Farmington, added that the study also provides a pathway to explore why cardiovascular complications could be occurring in patients with cancer who are treated with checkpoint blockers.
“We also think the work can inform the cardiovascular field of the role of immune checkpoint molecules in inflammation and cholesterol metabolism,” she said.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Mulholland M, Kritikou E, Katra P, et al. LAG3 regulates T cell activation and plaque infiltration in atherosclerotic mice. JACC CardioOncol. 2022;4(5):635-645.