Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies.
adverse effects
cardiotoxicity
immune checkpoint inhibitors
immune system
lymphocyte
mechanisms
Journal
Vaccines
ISSN: 2076-393X
Titre abrégé: Vaccines (Basel)
Pays: Switzerland
ID NLM: 101629355
Informations de publication
Date de publication:
31 Mar 2022
31 Mar 2022
Historique:
received:
18
02
2022
revised:
15
03
2022
accepted:
24
03
2022
entrez:
23
4
2022
pubmed:
24
4
2022
medline:
24
4
2022
Statut:
epublish
Résumé
Adaptive immune response modulation has taken a central position in cancer therapy in recent decades. Treatment with immune checkpoint inhibitors (ICIs) is now indicated in many cancer types with exceptional results. The two major inhibitory pathways involved are cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1). Unfortunately, immune activation is not tumor-specific, and as a result, most patients will experience some form of adverse reaction. Most immune-related adverse events (IRAEs) involve the skin and gastrointestinal (GI) tract; however, any organ can be involved. Cardiotoxicity ranges from arrhythmias to life-threatening myocarditis with very high mortality rates. To date, most treatments of ICI cardiotoxicity include immune suppression, which is also not cardiac-specific and may result in hampering of tumor clearance. Understanding the mechanisms behind immune activation in the heart is crucial for the development of specific treatments. Histological data and other models have shown mainly CD4 and CD8 infiltration during ICI-induced cardiotoxicity. Inhibition of CTLA4 seems to result in the proliferation of more diverse T0cell populations, some of which with autoantigen recognition. Inhibition of PD-1 interaction with PD ligand 1/2 (PD-L1/PD-L2) results in release from inhibition of exhausted self-recognizing T cells. However, CTLA4, PD-1, and their ligands are expressed on a wide range of cells, indicating a much more intricate mechanism. This is further complicated by the identification of multiple co-stimulatory and co-inhibitory signals, as well as the association of myocarditis with antibody-driven myasthenia gravis and myositis IRAEs. In this review, we focus on the recent advances in unraveling the complexity of the mechanisms driving ICI cardiotoxicity and discuss novel therapeutic strategies for directly targeting specific underlying mechanisms to reduce IRAEs and improve outcomes.
Identifiants
pubmed: 35455289
pii: vaccines10040540
doi: 10.3390/vaccines10040540
pmc: PMC9031363
pii:
doi:
Types de publication
Journal Article
Review
Langues
eng
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