Science subjournal: Hormone therapy may reduce the risk of immunotherapy-related myocarditis in women

A new preclinical study conducted by researchers at the University of Texas MD Anderson Cancer Center and the University of California, San Francisco (UCSF) has found potential causes
of sex differences in immunotherapy-associated myocarditis after immune checkpoint inhibitor (ICI) therapy.
Their findings point to possible treatment strategies for this side effect, which disproportionately affects female patients
.

The study, published in Science Translational Medicine, shows how life-saving ICI treatment can reduce levels of estrogen and important cardioprotective proteins, sometimes leading to cardiovascular complications
.
The results suggest that several treatments, including hormone therapy, can target this endocrine-cardio-immune pathway without affecting treatment response
.

"Immune checkpoint inhibitors can save the lives of many patients, but increasing the dose or combining it with other therapies can also increase the risk of myocarditis, especially for women, and with this study, we now understand the mechanism behind this, and we have found several potential ways to reduce this risk without affecting the anti-tumor effect
of the treatment.
"

Immune checkpoint inhibitors produce a long-lasting antitumor response in many patients, but they are associated
with an increased risk of cardiovascular toxicity caused by immune cells that penetrate into the heart tissue.
Although this condition occurs in only about 1% of patients, these side effects can significantly increase mortality
in women.

To better understand the mechanisms behind these sex differences, Yang collaborated
with co-corresponding author Chunru Lin, MD, associate professor of molecular and cellular oncology at MD Anderson, and Javid Moslehi, MD, associate professor of cardiac oncology and immunology at UCSF's Center for Heart and Vessels.

Checkpoint blockade reduces the expression of cardioprotective genes, especially in women

MD Anderson researchers worked with Moslehi and his team at UCSF to develop laboratory models of melanoma, breast cancer, and colorectal cancer to study ICI-associated myocarditis
.
Treatment with commonly used ICIs (anti-PD-1 and anti-CTLA-4 antibodies) can inhibit tumor growth, but also increase immune cell infiltration, especially in the female heart, leading to myocarditis-related ECG abnormalities and systolic dysfunction
.

By studying these models, the team found that ICI treatment reduced genes in Manf and Hspa5 heart tissue, especially in women
.
Similarly, models Ctla4 and Pdcd1 cardio-invasive immune cells lacking immune checkpoint genes also had a significant increase in Manf and Hspa5.

Further investigation revealed a decrease in MANF and HSPA5 proteins and an increase in
immune cells in patients with myocardial infarction-related myocarditis compared to healthy donors.
These findings suggest that MANF and HSPA5 are involved in regulating the interaction
between the cardiovascular and immune systems.

The MANF and HSPA5 proteins in the infusion group reversed these effects and improved cardiac function without affecting the post-ICI anti-tumor response, emphasizing that this is a possible therapeutic strategy
.

ICI treatment affects sex hormone levels and suggests possible treatments

"The sex differences observed in the two ICI-myocarditis mouse models are particularly interesting because in non-ICI myocarditis (viral or autoimmune) in the general population, male sex is considered a risk factor and defines a more severe course of
the disease," Moslehi said.
"If there is such a heterosexual difference in myocarditis, it means that there may be an interaction
between immune checkpoints and sex hormones.
"

In fact, the researchers noted that after two weeks of ICI treatment, serum estrogen concentrations were significantly reduced in both men and women, accompanied by a downregulation of estrogen to Manf and Hspa5.

The use of estrogen receptor β (ERβ) agonists increases estrogen-dependent expression of Manf and Hspa5 results in decreased
tumor contraction and cardioinvasive immune cells after ICI treatment.
In contrast, androgen deprivation therapy increased the expression of these proteins and proved to be an alternative strategy
for mitigating myocarditis in laboratory models.

"Based on these results, we can envision several potential treatment strategies
.
" For example, we can consider monitoring a patient's estrogen levels after ICI treatment and possibly injecting them with recombinant MANF and HSPA5 proteins to restore their levels and improve outcomes
.
"Similarly, targeting ERβ agonists to increase Manf and Hspa5 expression, or to achieve the same effect by blocking androgens, may reduce the risk of adverse events, allowing us to tailor these strategies to the needs of individual patients, thereby optimizing the use of immunotherapy and minimizing
cardiotoxicity.
"

While this is a preclinical study, the authors are planning clinical trials to evaluate these methods
using drugs that have been approved by the Federal Drug Administration (FDA).

This work was supported by MD Anderson Agency Grants, the Cancer Prevention and Research Institute of Texas (CPRIT) (RP200423, RP180259), the American Association for Cancer Research (AACR)-Mark Cancer Research Science Foundation Patient Grant, National Institutes of Health (R01CA218025, R01CA231011, R01HL141466, R01HL155990, R01HL156021).
Support
with the US Department of Defense (BC180196).
The full list of co-authors and their disclosures can be found in the full paper
here.