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Immune checkpoints in cardiac physiology and pathology: therapeutic targets for heart failure

Nature Reviews Cardiology (2024)Cite this article

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Abstract

Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have revolutionized cancer treatment and their clinical use is increasing. However, ICIs can cause various immune-related adverse events, including acute and chronic cardiotoxicity. Of these cardiovascular complications, ICI-induced acute fulminant myocarditis is the most studied, although emerging clinical and preclinical data are uncovering the importance of other ICI-related chronic cardiovascular complications, such as accelerated atherosclerosis and non-myocarditis-related heart failure. These complications could be more difficult to diagnose, given that they might only be present alongside other comorbidities. The occurrence of these complications suggests a potential role of immune checkpoint molecules in maintaining cardiovascular homeostasis, and disruption of physiological immune checkpoint signalling might thus lead to cardiac pathologies, including heart failure. Although inflammation is a long-known contributor to the development of heart failure, the therapeutic targeting of pro-inflammatory pathways has not been successful thus far. The increasingly recognized role of immune checkpoint molecules in the failing heart highlights their potential use as immunotherapeutic targets for heart failure. In this Review, we summarize the available data on ICI-induced cardiac dysfunction and heart failure, and discuss how immune checkpoint signalling is altered in the failing heart. Furthermore, we describe how pharmacological targeting of immune checkpoints could be used to treat heart failure.

Key points

  • Immune checkpoint inhibitors have revolutionized cancer treatment, but their use is associated with immune-related adverse events, including cardiovascular adverse effects.

  • Among the cardiovascular adverse events associated with immune checkpoint inhibitors, myocarditis is the most studied, but heart failure is increasingly being recognized.

  • Immune checkpoint signalling is involved in several physiological and pathological processes in the heart.

  • Modulation of immune checkpoint signalling can result in cardiac dysfunction or provide a target for therapeutic interventions in the failing heart, depending on the targeted checkpoint.

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Fig. 1: Immune checkpoint molecules in T cell co-inhibition and co-stimulation.
Fig. 2: Clinical presentations of early-onset and late-onset immune checkpoint inhibitor-induced cardiotoxicity.
Fig. 3: Potential mechanisms of immune checkpoint inhibitor-induced cardiac dysfunction and fulminant myocarditis.
Fig. 4: The potential of immune checkpoint-targeted drugs for the treatment of heart failure.
Fig. 5: Functional characterization of immune checkpoint expression patterns in the healthy and the failing heart.

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Acknowledgements

Z.V.V. was supported by the EU Horizon 2020 Research and Innovation Programme (grant number 739593), by a Momentum Research Grant from the Hungarian Academy of Sciences, by a National Research, Development and Innovation Office under grant 2022-1.1.1-KK-2022-00005 and an EU grant on project RRF-2.3.1-21-2022-00003. T.G.G. was supported by the Semmelweis 250 + Excellence PhD Scholarship (EFOP-3.6.3-VEKOP-16-2017-00009) and by the Gedeon Richter Talentum Foundation scholarship. Z.D.D. and T.G.G. was supported by the ÚNKP-23-4-II-SE and ÚNKP-23-II-SE-43 New National Excellence Program of the Ministry for Innovation and Technology from the National Research, Development and Innovation fund, respectively. H.Z. is supported by grant funding from the National Institutes of Health and National Heart, Lung, and Blood Institute (K08HL161405). M.K. receives support from AIRC IG grant 24988. W.C.M. is supported by the Mandema–Stipendium of the Junior Scientific Masterclass 2020-10 of the University Medical Center Groningen and by the Dutch Heart Foundation (Dekker grant 03-005-2021-T005). T.G.N. is supported by a gift from A. Curt Greer and P. Kohlberg and from C. and P. Kazilionis, the Michael and Kathryn Park Endowed Chair in Cardiology, by a Hassenfeld Scholar Award, and has additional grant funding from the National Institutes of Health and National Heart, Lung, and Blood Institute (R01HL137562 and K24HL150238).

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Authors and Affiliations

  1. Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary

    Tamás G. Gergely, Péter Ferdinandy & Zoltán V. Varga

  2. HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary

    Tamás G. Gergely & Zoltán V. Varga

  3. MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary

    Tamás G. Gergely & Zoltán V. Varga

  4. Heart and Vascular Center, Semmelweis University, Budapest, Hungary

    Zsófia D. Drobni

  5. Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Zsófia D. Drobni & Tomas G. Neilan

  6. Department of Biomedical Sciences, Humanitas University, Milan, Italy

    Marinos Kallikourdis

  7. Adaptive Immunity Lab, Humanitas Research Hospital IRCCS, Milan, Italy

    Marinos Kallikourdis

  8. Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, USA

    Han Zhu

  9. Erasmus MC, Cardiovascular Institute, Thorax Center, Department of Cardiology, Rotterdam, The Netherlands

    Wouter C. Meijers

  10. Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center Essen, Medical Faculty, University Hospital Essen, Essen, Germany

    Tienush Rassaf

  11. Pharmahungary Group, Szeged, Hungary

    Péter Ferdinandy

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Contributions

T.G.G. researched data for the article. T.G.G. and Z.V.V. wrote the article. All authors contributed to the discussion of content and to reviewing and editing the manuscript before submission.

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Correspondence to Zoltán V. Varga.

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Competing interests

M.K. is listed as an inventor in a patent on the use of co-stimulation blockade in heart failure. W.C.M. received speaker fees from Daiichi Sankyo and Novartis. T.G.N. has been a consultant for and received fees from Bristol Myers Squibb, CRC Oncology, Genentech, Roche, Roivant, Sanofi and Race Oncology, and has received grant funding from AstraZeneca and Bristol Myers Squibb for work related to immune checkpoint inhibitors. T.R. is a co-founder of Bimyo, a company focusing on the development of cardioprotective peptides; is listed on patents for the use of BNIP3 peptides for the treatment of myocardial infarction; is listed on a patent on the transport and delivery of nitric oxide; and is also listed on a patent of an antihypertensive composition of nitrate or nitrate derivates. P.F. is the founder and CEO of the Pharmahungary Group, a group of research and development companies. All other authors declare no competing interests.

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Gergely, T.G., Drobni, Z.D., Kallikourdis, M. et al. Immune checkpoints in cardiac physiology and pathology: therapeutic targets for heart failure. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-023-00986-9

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