Which cells drive myocarditis in cancer patients?

In a new study, researchers from UCSF and Vanderbilt University Medical Center identified specific immune cells
that cause deadly heart inflammation in a small subset of patients treated with powerful cancer immunotherapy.
The researchers have also identified cells in the heart muscle as targets for damaging immune cells, and their new findings have led them to begin investigating better ways
to prevent or treat this potentially deadly inflammation of the heart — myocarditis.

The myocarditis they studied is a rare but fatal side effect
of cancer immunotherapy drugs immune checkpoint inhibitors (ICIs).

ICIs target proteins in the body that act as gatekeepers of the immune system's response and control unwanted inflammation
.
But blocking these checkpoint proteins with ICIs suppresses the immune response, helping the immune system effectively attack tumors
that have formed.
ICI treatment has been shown to save the lives
of many cancer patients.

According to Javid Moslehi, MD, special professor William Grossman and director of the Division of Cardiac Oncology and Immunology at the UCSF Center for Heart and Vascular Diseases, less than 1 percent of patients treated with checkpoint inhibitors (first approved in 2011) develop myocarditis, but nearly half of those with this inflammatory immune response die
as a result.

Moslehi co-led the new study, which was published Nov.
16, 2022, in the journal Nature
, with Justin Balko, an associate professor of medicine and pathology at Vanderbilt University and a cancer biologist.
They first described the clinical symptoms of myocardial infarction-myocarditis in 2016
.
In the new study, to mimic ICIs-induced human myocarditis, the researchers used a mouse strain in which human proteins targeted by ICIs were knocked out
by genes.
They found that in the inflammatory heart tissue of mice with myocarditis, immune system cells called CD8 T lymphocytes predominated
.

The researchers concluded that these activated T cells are necessary to trigger myocarditis, so immunosuppressive therapies that affect CD8 T cells may play a beneficial role
.

"We observed many T cells earlier in dead patients, but in mice we performed several key experiments to show that T lymphocytes are indeed drivers of the disease process, not just innocent bystanders
," Moslehi said.
This research has therapeutic implications
.
”

The research team has reported a case study in which they successfully treated myocarditis
in a cancer patient using Abatacept, a rheumatoid arthritis drug that inhibits CD8 T cell activation.

In the Nature study, the scientists also found that CD8 T cells, which are selectively activated and proliferate in myocarditis, are those that target the α-myosin heavy chain (α-MHC), a key protein involved in heart muscle contraction
.

The researchers then examined the biopsy and autopsy tissue of three cancer patients with myocarditis who had been treated with ICI and determined that in humans, the CD8 T cells that cloned and expanded the most were also cells
that targeted α-MHC.

"Interestingly, in the affected heart, the T-cell receptors (basically the identity barcodes of T lymphocytes) that target α-MHC are identical, meaning they may pursue the same goals
," Balko said.

The researchers are testing T-cell-targeted therapies and conducting studies to see if activation of CD8 T cells in myocarditis, induced by myocardial infarction, also stimulates the immune system to produce antibody B cells, targeting
α-MHC.
Researchers are figuring out ways to get the immune system to stop attacking α MHC, through a tolerance process similar to how allergy vaccines work
.

T cells specific for α-myosin drive immunotherapy-related myocarditis