HMN 2026: why cancer immunotherapy leads to heart inflammation

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by using the 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 of targeting proteins LAG-3 and PD-1, according to new research.

In a study led by UC San Francisco researchers that published in Circulation, the investigators 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. They subsequently generated a genetic mouse model that mimicked anti-LAG-3/anti-PD-1 myocarditis to better define the immune cell types that drive ICI-myocarditis. In the murine model, development of severe cardiac inflammation with increased cardiac macrophages and clonal T-cells was associated with the development of spontaneous arrhythmias.

Importantly, the investigators identified CXCR6, a chemokine receptor expressed on activated T-lymphocytes, as being critical in the development of myocarditis. In the mouse model, severe cardiac inflammation, spontaneous arrhythmias and premature death were prevented by treatment with an antibody against CXCR6. And using available patient data, they were able to show CXCR6+ T-cells also increased in the hearts of patients who developed ICI-myocarditis—identifying CXCR6 as 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 cardiac T-cell populations 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.

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