In groundbreaking research at ChristianaCare’s Helen F. Graham Cancer Center & Research Institute, scientists have discovered that a protein secreted by tumor cells can shut down the body’s natural defenses against triple negative breast cancer (TNBC).
The study, led by Jennifer Sims-Mourtada, Ph.D., senior research scientist at the Cawley Center for Translational Cancer Research (CTCR) at Graham Cancer Center, is reported in The Journal of Translational Medicine, available online.
“What we found is that TNBC tumor cells can effectively turn off the body’s defenses against the tumor by secreting a type of protein called IL-10,” said Dr. Sims Mourtada.
“The presence of this immune system protein forces the antibodies that would normally be made to attack the tumor to stop responding and not doing what they are supposed to do.”
The study was initiated in partnership with the Wistar Institute of Philadelphia, Pennsylvania, in collaboration with the late Raj “Shyam” Somasundaram, Ph.D., a cell biologist at the Melanoma Research Center.
“DR. Sims-Mourtada and her team have tantalizingly brought us closer to understanding what drives the aggressive nature of triple-negative breast cancer, a treatment-poor disease that disproportionately affects women in Delaware,” said Nicholas J. Petrelli, MD , Bank of America Foundation Director of the Helen F. Graham Cancer Center & Research Institute.
“Their work underscores our belief that scientific collaborations like this between our Cawley CTCR clinicians and Wistar scientists can pave the way for new discoveries to become effective therapies, particularly for difficult-to-treat and aggressive cancers like TNBC.”
Understand the mechanism behind TNBC
Delaware ranks highest nationwide for the incidence of triple-negative breast cancer. TNBC is an aggressive form that affects black women twice as often as white women with poorer outcomes. Patients have higher rates of early recurrence than other breast cancer subtypes, especially in the first five years after diagnosis. There is currently no targeted therapy for TNBC.
“One of our missions within the Cawley CTCR is to understand the mechanisms behind TNBC and find a treatment for it,” said Dr. Sims Mourtada. “Our study sheds new light on what triggers the body’s immune response to cancer cells and provides clues to potential new therapeutic targets.”
Normally, the job of the B cells is to regulate the immune response against foreign invaders such as cancer. Among other things, they control inflammation at the site of an attack by releasing proteins, including IL-10, to signal defense cells to retreat.
“It used to be thought that the immune cells are the ones that express IL-10 to regulate themselves,” said Dr. Sims Mourtada. “But our study shows that the tumor cells also secrete this protein, which means that they control the behavior of the immune system.”
Within the tumor microenvironment, IgG4 is one of four antibody subclasses expressed and secreted by B cells. While another type of antibody would urge the immune system to continue attacking, activating IgG4 signals that the job is done.
TNBC and activation of IgG4
“Our results support that TNBC may create a tumor environment that supports IgG4 activation and that IL10 messaging triggers the switch,” said Dr. Sims Mourtada.
As previously reported in other cancers such as melanoma, this study confirms that the presence of IgG4-positive B cells in the tumor is associated with advanced disease, increased recurrence and poor overall survival in breast cancer. It is also possible that IL-10 expression by tumor cells may also be a cause of poor outcomes in TNBC, and this may be independent of IgG4+ B cells.
“At this time, we don’t know what triggers tumor cells to start secreting IL-10, but we do know that interactions between B cells and tumor cells are involved,” said Dr. Sims Mourtada.
“We still need to look at what’s really going on in the B cell population to determine which subtypes of B cells are affected by this tumor crosstalk and why some forms of TNBC express IL-10 (the ones with bad results) and others do not.
“We think that the presence or absence of other immune cells in the microenvironment can affect how B cells interact with tumor cells to drive IL-10 expression,” she said.
Resources for the study, including blood and tissue samples from consenting patients, were obtained through the Graham Cancer Center’s Tissue Procurement Program. Interestingly, in a small subset of samples, the researchers found that IL-10 expression was significantly higher in black patients than in non-Hispanic white patients. These results need to be confirmed in a larger, more diverse population with different TNBC subtypes.
Understanding tumor-infiltrating B cells
“Our growing understanding of the contribution of IgG4+ cells to the immune microenvironment of TNBC and what drives IL-10 expression may shed light on ways in which tumor-infiltrating B cells may contribute to tumor growth and provide new targets to enhance the immune response to TNBC,” said Dr. Sims Mourtada.
As partners, Graham Cancer Center research clinicians and Wistar scientists have worked together across disciplines for more than a decade to translate cancer research into more effective therapies for patients around the world. In addition to providing high-quality, viable tissue samples for Wistar research studies, Graham Cancer Center clinicians actively participate in concept development and share their unique understanding of the everyday patient experience.