Cancer Immunotherapy's Hidden Risk: Why Some Patients Develop Heart Inflammation

A groundbreaking study has identified why some cancer immunotherapy combinations cause potentially fatal heart inflammation, revealing that anti-LAG-3/anti-PD-1 therapy increases the risk of cardiac complications four-fold compared to single-drug treatments. Researchers at UC San Francisco have also discovered a specific protein that could serve as a new treatment target for this dangerous side effect.

What Makes This Immunotherapy Combination So Risky?

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by unleashing a patient's own T-cells to attack tumors. However, the most recent combination therapy—anti-LAG-3/anti-PD-1—carries significantly higher risks than older treatments. Using a global pharmacovigilance database called Vigibase, researchers found this combination therapy quadruples the risk of developing ICI-myocarditis, a rare but potentially deadly form of heart inflammation.

The research team, led by cardiologist Dr. Amir Munir from UCSF's Section of Cardio-Oncology and Immunology, used both human patient data and mouse studies to understand why this happens. In mice receiving the combination therapy, severe cardiac inflammation led to spontaneous heart rhythm problems—a finding that mirrors what doctors see in affected patients.

How Does the Heart Inflammation Actually Develop?

The key breakthrough came when researchers discovered that cardiac T-cells in affected hearts express high levels of a protein called CXCR6. This protein acts like a GPS system for immune cells, directing their movement and regulating inflammatory responses throughout the body. In both mouse studies and human patient data, CXCR6-expressing T-cells accumulated specifically in heart tissue during immunotherapy-related inflammation.

The research team's findings revealed several critical mechanisms behind this dangerous side effect:

• Protein Expression: T-cells infiltrating the heart during anti-LAG-3/anti-PD-1 myocarditis specifically express CXCR6, which wasn't seen with other immunotherapy combinations
• Cardiac Targeting: CXCR6 acts as a homing signal that recruits and positions inflammatory T-cells directly in heart muscle tissue
• Rhythm Disruption: The resulting inflammation causes spontaneous arrhythmias that can be life-threatening without immediate medical intervention

Could This Discovery Lead to Better Treatments?

Perhaps most importantly, when researchers used antibodies to block CXCR6 in their mouse studies, they successfully reduced both cardiac inflammation and dangerous heart rhythm problems. This suggests that targeting CXCR6 could offer a way to prevent or treat immunotherapy-related heart complications without compromising cancer treatment effectiveness.

"These data are particularly exciting and help us understand the signals that recruit and position T-cells in the heart," said Dr. Amir Munir, the study's co-first and co-corresponding author. "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."

The research, published January 7 in Circulation, opens new possibilities for protecting cancer patients from serious cardiac side effects. Dr. Munir notes that while this study focused specifically on immunotherapy-related heart inflammation, the same T-cell population might drive other forms of cardiac inflammation as well. However, researchers emphasize the need to understand how blocking CXCR6 might affect the immune system's ability to fight cancer before this approach can be tested in patients.

This discovery represents a significant step forward in making cancer immunotherapy safer, potentially allowing more patients to benefit from these life-saving treatments without facing dangerous cardiac complications.