Hormone therapy could lower risk of immunotherapy-associated myocarditis in women: Study uncovers reason for sex differences and identifies specific targets for improving treatment efficacy

A new preclinical study from researchers at The University of Texas MD Anderson Cancer Center and the University of California San Francisco (UCSF) has discovered the underlying cause of gender differences in immunotherapy-associated myocarditis after immune checkpoint inhibitor (ICI) treatment. Their findings point to possible treatment strategies for this side effect, which disproportionately affects female patients.

The study, published today in Science Translational Medicine, demonstrates how life-saving ICI treatment reduces levels of estrogen and important heart-protective proteins, sometimes leading to cardiovascular complications. The results suggest several treatment approaches, including hormone therapies, that could target this endocrine-cardiac-immune pathway without affecting treatment responses.

“Immune checkpoint inhibitors can be life-saving for many patients, but increasing the dose or combining with other therapies also increases the risk for myocarditis, particularly in women,” said co-corresponding author Liuqing Yang, Ph.D., associate professor of Molecular and Cellular Oncology. “With this study, we now understand the mechanisms behind this, and we’ve found several potential ways to reduce this risk without compromising the antitumor effects of treatment.”

Immune checkpoint inhibitors result in durable anti-tumor responses in many patients, but they are associated with an increased risk of cardiovascular toxicities caused by immune cells that infiltrate heart tissue. While this occurs in only about 1% of patients, these side effects can significantly increase the mortality rate in women.

To better understand the mechanisms behind these gender differences, Yang worked with co-corresponding authors Chunru Lin, M.D., Ph.D., associate professor of Molecular and Cellular Oncology at MD Anderson, and Javid Moslehi, M.D., associate professor of Cardio-Oncology and Immunology for the UCSF Heart and Vascular Center.

Checkpoint blockade reduces expression of heart-protective genes, particularly in females

MD Anderson researchers collaborated with Moslehi and his team at UCSF to develop laboratory models of melanoma, breast and colorectal cancer to study ICI-associated myocarditis. Treatment with commonly used ICIs (anti-PD-1 and anti-CTLA-4 antibodies) inhibited tumor growth but also increased immune cell infiltration, particularly in female hearts, causing electrocardiographic abnormalities and systolic dysfunction associated with myocarditis.

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