Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies
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 pr...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/10/4/540 |
| _version_ | 1797443299173203968 |
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| author | Daniel Ronen Aseel Bsoul Michal Lotem Suzan Abedat Merav Yarkoni Offer Amir Rabea Asleh |
| author_facet | Daniel Ronen Aseel Bsoul Michal Lotem Suzan Abedat Merav Yarkoni Offer Amir Rabea Asleh |
| author_sort | Daniel Ronen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T12:53:58Z |
| format | Article |
| id | doaj.art-7ea0ca1334004c4e8d6e4af0ee8d5817 |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-09T12:53:58Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-7ea0ca1334004c4e8d6e4af0ee8d58172023-11-30T22:02:03ZengMDPI AGVaccines2076-393X2022-03-0110454010.3390/vaccines10040540Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor TherapiesDaniel Ronen0Aseel Bsoul1Michal Lotem2Suzan Abedat3Merav Yarkoni4Offer Amir5Rabea Asleh6Department of Internal Medicine D, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, IsraelCardiovascular Research Center, Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, IsraelDepartment of Oncology, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, IsraelCardiovascular Research Center, Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, IsraelDepartment of Cardiology, Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, IsraelCardiovascular Research Center, Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, IsraelCardiovascular Research Center, Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, IsraelAdaptive 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.https://www.mdpi.com/2076-393X/10/4/540immune checkpoint inhibitorscardiotoxicitylymphocyteimmune systemmechanismsadverse effects |
| spellingShingle | Daniel Ronen Aseel Bsoul Michal Lotem Suzan Abedat Merav Yarkoni Offer Amir Rabea Asleh Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies Vaccines immune checkpoint inhibitors cardiotoxicity lymphocyte immune system mechanisms adverse effects |
| title | Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies |
| title_full | Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies |
| title_fullStr | Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies |
| title_full_unstemmed | Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies |
| title_short | Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies |
| title_sort | exploring the mechanisms underlying the cardiotoxic effects of immune checkpoint inhibitor therapies |
| topic | immune checkpoint inhibitors cardiotoxicity lymphocyte immune system mechanisms adverse effects |
| url | https://www.mdpi.com/2076-393X/10/4/540 |
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