Uncovering Why Cancer Immunotherapy Leads to Heart Inflammation
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by using a patient’s own T-cells to target tumors. However, they can cause rare but potentially fatal cardiac inflammation known as ICI-myocarditis. This is particularly true in the most recent ICI combination treatment, according to new research.
In a study led by UC San Francisco researchers that published Jan. 7 in Circulation, the researchers found that anti-LAG-3/anti-PD-1 combination therapy shows a higher risk of myocarditis compared to other ICI treatments.
Using Vigibase, a pharmacovigilance database, the team first determined that anti-LAG-3/anti-PD-1 therapy increased the risk of ICI myocarditis four-fold in human patients compared to anti-PD-1 therapy alone. Investigating further using mice with anti-LAG-3/anti-PD-1 myocarditis, the researchers saw that the resulting severe cardiac inflammation was associated with spontaneous arrhythmias.
Importantly, in mice with anti-LAG-3/anti-PD-1 myocarditis, researchers discovered that the cardiac T-cells expressed CXCR6, a protein that directs cell movement and regulates immune responses and inflammation. By targeting CXCR6 with an antibody, researchers were able to reduce cardiac inflammation and spontaneous arrhythmias. With this new knowledge, the researchers turned back to patients. Using available patient data, they were able to show CXCR6 T-cells also increased in the hearts of patients who developed ICI-myocarditis — meaning CXCR6 could be a possible target for treatment.
“These data are particularly exciting and help us understand the signals that recruit and position T-cells in the heart,” said study co-first and co-corresponding author Amir Munir, MD, a cardiologist and instructor in the UCSF Section of Cardio-Oncology and Immunology. “The results help define the specific type of cardiac T-cells that lead to myocarditis and may serve as a potential therapeutic target for treating ICI-myocarditis in the future.”
Munir adds that while the investigators studied ICI-myocarditis in the current study, it is possible that this same T-cell population may drive other forms of cardiac inflammation. “An important next question to address will be understanding the role CXCR6 T-cells in anti-tumor immunity, especially if we think this could be a possible therapeutic option for patients with ICI myocarditis,” said Munir.
Additional Authors: Alan Gutierrez, BA; Cade J. Krawiec, BS; Priyanka Manandhar, PhD; Anya C. Shyani; Pan Ma, PhD; Paul Gougis, MD; Richard A. Baylis, MD, PhD; Lifei Hou, PhD; Eileen Remold-O’Donnell PhD; Justin M. Balko, PharmD, PhD; Joe-Elie Salem, MD, PhD; Kory J. Lavine, MD, PhD; Andrew H. Lichtman, MD, PhD; Juan Qin, PhD, and Javid J. Moslehi, MD.
Funding: A.Z.M. is supported by the Sarnoff Cardiovascular Research Foundation Scholar Program and Chan-Zuckerberg Biohub SF Physician Scientist Fellowship Program. A.G. is supported by the Sarnoff Cardiovascular Research Foundation Fellowship Program. P. Ma is supported by funding provided by the National Institutes of Health (NIH; grant 1K99HL171935-01A1). K.L. is supported by the Washington University in St. Louis Rheumatic Diseases Research Resource-Based Center (grant NIH P30AR073752), the NIH (grants R01 HL138466, R01 HL139714, 639 R01 HL151078, R01 HL161185, and R35 HL161185), the Leducq Foundation Network (grant 20CVD02), the Burroughs Welcome Fund (grant 1014782), the Children’s Discovery Institute of Washington 641 University and St. Louis Children’s Hospital (grants CH-II-2015-462, CH-II-2017-628, and PM-LI-2019-829), the Foundation of Barnes-Jewish Hospital (grant 8038-88), the Myocarditis Foundation, and generous gifts from the Washington University School of Medicine. J.Q. is supported by 2024 UCSF Catalyst Award 7032062 and AHA’s Second Century Early Faculty Independence Award 24SCEFIA1246915. J.J.M. is supported by National Institutes of Health (NIH) grants R01HL155990, R01HL156021, R01HL160688, R01HL170038 and P01HL141084.
Disclosures: A.Z.M. and J.J.M. are listed as inventors on a provisional patent application relating to the therapeutic use of anti-CXCR6 for the treatment of myocarditis.
About UCSF Health: UCSF Health is recognized worldwide for its innovative patient care, reflecting the latest medical knowledge, advanced technologies and pioneering research. It includes the flagship UCSF Medical Center, which is a highly-ranked specialty hospital, as well as UCSF Benioff Children’s Hospitals, with campuses in San Francisco and Oakland; two community hospitals, UCSF Health Stanyan and UCSF Health Hyde; Langley Porter Psychiatric Hospital; UCSF Benioff Children’s Physicians; and the UCSF Faculty Practice. These hospitals serve as the academic medical center of the University of California, San Francisco, which is world-renowned for its graduate-level health sciences education and biomedical research. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. Visit www.ucsfhealth.org. Follow UCSF Health on Facebook or on Twitter.