Researchers may have discovered the underlying cause of sex differences in immune checkpoint inhibitor–associated myocarditis after immune checkpoint inhibitor treatment, according to a novel study published by Zhang et al in Science Translational Medicine. Their findings pointed to possible treatment strategies for this side effect, which disproportionately affects female patients.
The preclinical study demonstrated how immune checkpoint inhibitor treatment also reduces levels of estrogen and important heart-protecting proteins, sometimes leading to cardiovascular complications. The results suggested several treatment approaches—including hormone therapies—that could target this endocrine-cardiac immune pathway without affecting treatment responses.
Research Background
Immune checkpoint inhibitors result in durable antitumor responses in many patients, but they are also associated with an increased risk of cardiovascular toxicities caused by immune cells that infiltrate the heart tissue. While this occurs in only about 1% of patients, these side effects can significantly increase the mortality rate in female patients.
“Immune checkpoint inhibitors can be life-saving for many patients, but increasing the dose or combining [them] with other therapies also increases the risk [of] myocarditis, particularly in women,” said co-corresponding study author Liuqing Yang, PhD, Associate Professor of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center. “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,” Dr. Yang highlighted.
Checkpoint Blockade Reduces Expression of Heart-Protective Genes, Particularly in Female Patients
To study immune checkpoint inhibitor–associated myocarditis and better understand the mechanisms behind these sex differences, Dr. Yang and colleagues developed laboratory models of melanoma, breast cancer, and colorectal cancer. Treatment with commonly used immune checkpoint inhibitors—anti–PD-1 and anti–CTLA-4 antibodies—repressed tumor growth but also increased immune-cell infiltration, particularly in the hearts of female patients, causing electrocardiographic abnormalities and systolic dysfunction associated with myocarditis.
By studying these models, the researchers discovered that immune checkpoint inhibitor treatment decreased expression of MANF and HSPA5 genes in the heart tissue, particularly in female patients. Similarly, models lacking the immune checkpoint genes CTLA-4 and PDCD1 also had a pronounced increase in heart-infiltrating immune cells and a lower expression of MANF and HSPA5 genes.
Further investigation revealed the same pattern in patients with immune checkpoint inhibitor–associated myocarditis, where MANF and HSPA5 proteins were decreased and immune cells were elevated compared with the protein- and immune cell–levels of healthy donors. These findings suggested that MANF and HSPA5 proteins were involved in regulating interactions between the cardiovascular system and the immune system.
Infusions of recombinant MANF and HSPA5 proteins reversed these effects, improving cardiac function without affecting antitumor response after immune checkpoint inhibitors, highlighting this as a possible therapeutic strategy.
Immune Checkpoint Inhibitor Treatment May Influence Sex Hormone Levels, Suggesting Possible Treatment Approaches
“The sex differences observed in both [immune checkpoint inhibitor–associated] myocarditis mouse models are especially intriguing because in non–[immune checkpoint inhibitor–associated] myocarditis (viral or autoimmune) in the general population, male sex is considered a risk factor and defines a more severe course,” outlined Javid Moslehi, MD, Associate Professor of Medicine and Chief of the Cardio-Oncology and Immunology Section at the University of California, San Francisco Heart and Vascular Center. “If such an opposite sex difference in [immune checkpoint inhibitor–associated] myocarditis is true, it suggests a possible interaction of immune checkpoints and sex hormones.”
The researchers noted that serum concentrations of estrogen were significantly reduced in both male and female patients 2 weeks after immune checkpoint inhibitor treatment, along with downregulation of MANF and HSPA5 genes.
Using an estrogen receptor beta agonist to increase the estrogen-dependent expression of MANF and HSPA5 genes resulted in tumor shrinkage and a decrease in heart-infiltrating immune cells following immune checkpoint inhibitor treatment. Conversely, androgen-deprivation therapy increased the expression of these proteins and proved successful in laboratory models as an alternative strategy to lessen myocarditis.
“Based on these results, we can envision several potential treatment strategies. For example, we may consider monitoring estrogen levels in patients after [immune checkpoint inhibitor] treatment and potentially infusing them with recombinant MANF and HSPA5 proteins to bring their levels back up and improve outcomes,” explained Chunru Lin, MD, PhD, Associate Professor of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center and Associate Professor of the Graduate School of Biomedical Sciences at The University of Texas Health Science Center. “Likewise, targeting with an [estrogen receptor beta] agonist to increase expression of MANF and HSPA5 [genes], or blocking androgens to do the same, might reduce the risk of adverse events, allowing us to tailor these strategies to individual patient needs so we can optimize the use of immunotherapy and minimize cardiac toxicities,” Dr. Lin concluded.
The study authors plan to evaluate these approaches using drugs already approved by the U.S. Food and Drug Administration in further clinical trials.
Disclosure: The research in this study was supported by institutional funding from The University of Texas MD Anderson Cancer Center, the Cancer Prevention and Research Institute of Texas (CPRIT), the American Association for Cancer Research (AACR)-The Mark Foundation for Cancer Research “Science of the Patient” Grant, the National Institutes of Health (NIH), and the U.S. Department of Defense. For full disclosures of the study authors, visit science.org.
