Immune Checkpoint Landscape of Human Atherosclerosis and Influence of Cardiometabolic Factors

Overview

Journal Nat Cardiovasc Res

Publisher Springer Nature

Specialty Cardiology & Vascular Diseases

Date 2024 Nov 29

PMID 39613875

Authors

Jose Gabriel Barcia Duran

Dayasagar Das

Michael Gildea

Letizia Amadori

Morgane Gourvest

Ravneet Kaur

Natalia Eberhardt

Panagiotis Smyrnis

Burak Cilhoroz

Swathy Sajja

Karishma Rahman

Dawn M Fernandez

Peter Faries

Navneet Narula

Rami Vanguri

Ira J Goldberg

Edward A Fisher

Jeffrey S Berger

Kathryn J Moore

Chiara Giannarelli

Affiliations

Soon will be listed here.

Abstract

Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7FSCN1 dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors.

Citing Articles

Characterizing Cardiotoxicity of FDA-Approved Soft Tissue Sarcoma Targeted Therapies and Immune Checkpoint Inhibitors: A Systematic Review.

Houmsse M, Muskara A, Pasca D, Roy A, Sughra S, Ghazi S Cancers (Basel). 2025; 17(5).

PMID: 40075674 PMC: 11899116. DOI: 10.3390/cancers17050827.

Unrestrained cancer immunity ignites atherosclerosis.

Williams J, Lutgens E Nat Cardiovasc Res. 2024; 3(12):1380-1382.

PMID: 39613874 DOI: 10.1038/s44161-024-00571-4.

References

Vuong J, Stein-Merlob A, Nayeri A, Sallam T, Neilan T, Yang E . Immune Checkpoint Therapies and Atherosclerosis: Mechanisms and Clinical Implications: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022; 79(6):577-593. PMC: 8983019. DOI: 10.1016/j.jacc.2021.11.048. View

Tawbi H, Schadendorf D, Lipson E, Ascierto P, Matamala L, Castillo Gutierrez E . Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022; 386(1):24-34. PMC: 9844513. DOI: 10.1056/NEJMoa2109970. View

Haslam A, Prasad V . Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs. JAMA Netw Open. 2019; 2(5):e192535. PMC: 6503493. DOI: 10.1001/jamanetworkopen.2019.2535. View

Zhang L, Reynolds K, Lyon A, Palaskas N, Neilan T . The Evolving Immunotherapy Landscape and the Epidemiology, Diagnosis, and Management of Cardiotoxicity: Primer. JACC CardioOncol. 2021; 3(1):35-47. PMC: 8034586. DOI: 10.1016/j.jaccao.2020.11.012. View

Suero-Abreu G, Zanni M, Neilan T . Atherosclerosis With Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: State-of-the-Art Review. JACC CardioOncol. 2023; 4(5):598-615. PMC: 9830225. DOI: 10.1016/j.jaccao.2022.11.011. View

Drobni Z, Alvi R, Taron J, Zafar A, Murphy S, Rambarat P . Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque. Circulation. 2020; 142(24):2299-2311. PMC: 7736526. DOI: 10.1161/CIRCULATIONAHA.120.049981. View

Herrmann J, Lenihan D, Armenian S, Barac A, Blaes A, Cardinale D . Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2021; 43(4):280-299. PMC: 8803367. DOI: 10.1093/eurheartj/ehab674. View

Poels K, van Leent M, Boutros C, Tissot H, Roy S, Meerwaldt A . Immune Checkpoint Inhibitor Therapy Aggravates T Cell-Driven Plaque Inflammation in Atherosclerosis. JACC CardioOncol. 2021; 2(4):599-610. PMC: 8352210. DOI: 10.1016/j.jaccao.2020.08.007. View

Bu D, Tarrio M, Maganto-Garcia E, Stavrakis G, Tajima G, Lederer J . Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol. 2011; 31(5):1100-7. PMC: 3104026. DOI: 10.1161/ATVBAHA.111.224709. View

10.

Fernandez D, Rahman A, Fernandez N, Chudnovskiy A, Amir E, Amadori L . Single-cell immune landscape of human atherosclerotic plaques. Nat Med. 2019; 25(10):1576-1588. PMC: 7318784. DOI: 10.1038/s41591-019-0590-4. View

11.

Mulholland M, Kritikou E, Katra P, Nilsson J, Bjorkbacka H, Lichtman A . LAG3 Regulates T Cell Activation and Plaque Infiltration in Atherosclerotic Mice. JACC CardioOncol. 2023; 4(5):635-645. PMC: 9830219. DOI: 10.1016/j.jaccao.2022.09.005. View

12.

Krautter F, Hussain M, Zhi Z, Lezama D, Manning J, Brown E . Galectin-9: A novel promoter of atherosclerosis progression. Atherosclerosis. 2022; 363:57-68. DOI: 10.1016/j.atherosclerosis.2022.11.014. View

13.

Jarr K, Nakamoto R, Doan B, Kojima Y, Weissman I, Advani R . Effect of CD47 Blockade on Vascular Inflammation. N Engl J Med. 2021; 384(4):382-383. PMC: 8175009. DOI: 10.1056/NEJMc2029834. View

14.

Kojima Y, Volkmer J, McKenna K, Civelek M, Lusis A, Miller C . CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature. 2016; 536(7614):86-90. PMC: 4980260. DOI: 10.1038/nature18935. View

15.

Gyldenkerne C, Mortensen M, Kahlert J, Thrane P, Olesen K, Sorensen H . 10-Year Cardiovascular Risk in Patients With Newly Diagnosed Type 2 Diabetes Mellitus. J Am Coll Cardiol. 2023; 82(16):1583-1594. DOI: 10.1016/j.jacc.2023.08.015. View

16.

Wang Z, Zhang X, Lu S, Zhang C, Ma Z, Su R . Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis. Nat Cardiovasc Res. 2023; 2(3):290-306. PMC: 10448629. DOI: 10.1038/s44161-023-00218-w. View

16.

Wu S, Zhang S, Ma D, Xiao Y, Liu Y, Chen L . CCL19 dendritic cells potentiate clinical benefit of anti-PD-(L)1 immunotherapy in triple-negative breast cancer. Med. 2023; 4(6):373-393.e8. DOI: 10.1016/j.medj.2023.04.008. View

17.

Dominguez Conde C, Xu C, Jarvis L, Rainbow D, Wells S, Gomes T . Cross-tissue immune cell analysis reveals tissue-specific features in humans. Science. 2022; 376(6594):eabl5197. PMC: 7612735. DOI: 10.1126/science.abl5197. View

18.

Bottcher J, Beyer M, Meissner F, Abdullah Z, Sander J, Hochst B . Functional classification of memory CD8(+) T cells by CX3CR1 expression. Nat Commun. 2015; 6:8306. PMC: 4667439. DOI: 10.1038/ncomms9306. View

19.

Depuydt M, Prange K, Slenders L, Ord T, Elbersen D, Boltjes A . Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics. Circ Res. 2020; 127(11):1437-1455. PMC: 7641189. DOI: 10.1161/CIRCRESAHA.120.316770. View