In a multidisciplinary collaboration, researchers at Vanderbilt University Medical Center and the University of Miami Miller School of Medicine have identified a subtype of triple-negative breast cancer (TNBC) that appears to be able to escape detection by the immune system and evade immunotherapy.
Their report, published Nov. 1 in the journal Nature Communications, provides further evidence that TNBC is not one but many different diseases and suggests that anti-cancer drugs called epigenetic inhibitors could improve treatment outcomes.
“As a whole, these studies show that triple-negative breast cancer needs to be considered as a multitude of diseases that require distinct therapeutic strategies,” said Brian Lehmann, PhD, research associate professor of Medicine in the Vanderbilt-Ingram Cancer Center (VICC).
Lehmann is the paper’s co-corresponding author with former Vanderbilt faculty member Xi Steven Chen, PhD, professor of Biostatistics at the University of Miami Miller School of Medicine. Both have worked with co-author and VICC director Jennifer Pietenpol, PhD, for more than a decade to unravel the mysteries of TNBC.
“From a long-standing multidisciplinary collaborative team, this study represents another critical step in our deciphering the molecular heterogeneity of TNBC,” said Pietenpol, who also is
Executive Vice President for Research at VUMC, Benjamin F. Byrd Jr. Professor of Oncology and holder of the Brock Family Directorship in Career Development.
“The discoveries were made possible through the robust integration of data science and bench-based experiments and, importantly, will provide pre-clinical insights for designing new treatment strategies for patients,” she said.
About 15% of breast cancers are called “triple-negative” because they lack the expression of estrogen and progesterone receptors and the human epidermal growth factor receptor 2 (HER2) protein. These cancers, which do not respond to hormonal therapy or drugs that target HER2, are particularly aggressive and difficult to treat.
Pathologists for years have noted that different TNBCs look different under the microscope. In 2011, Lehmann, Chen, Pietenpol and their colleagues confirmed these observations in several influential papers describing the unique biology of TNBC subtypes and their differential response to standard chemotherapy.
In 2016 they reported a TNBC subtype named for its resemblance to mesenchymal stem cells lacked infiltrating immune cells, despite having a high mutational “load” and genomic instability that usually would trigger an immune attack. This suggests the mesenchymal (M) subtype has developed a way to evade the immune system.
Most tumor cells are recognized and killed by infiltrating immune cells, called T cells. Some, however, can evade immune detection. And if tumors grow rapidly enough, they can outpace the ability of T cells to bring them under control.
Recently a new class of drugs, called immune checkpoint inhibitors, has shown promise in treating various forms of cancer. These drugs prevent T cells from being “turned off” when their surface “checkpoint” protein binds to a “partner” protein called PD-L1 on the tumor surface.
Roughly one-third of TNBCs respond to checkpoint inhibitors. Those most likely to respond have high mutational burdens or express the T-cell “off-switch,” PD-L1. M subtype tumors typically express low levels PD-L1 and lack infiltrating T-cells, likely rendering them unresponsive to checkpoint inhibitors.
To find out how mesenchymal tumors elude immune detection, the researchers conducted a comprehensive, “multi-omic” and subtype-specific analysis of tissue samples from TNBC patients included in The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium.
Supported by the National Institutes of Health (NIH), these projects provide extensive data about the expression of tumor-related genes and proteins.
The analysis revealed an important clue: the M subtype represses the expression of specific protein markers that present tumor antigens on the tumor cell surface. These surface markers enable the immune system to distinguish normal cells from cancerous ones.
Specifically, proteins in what’s called the polycomb repressor complex 2 (PRC2) repress expression of antigen-presenting, major histocompatibility complex class I (MHC-I) genes.
The resulting lack of surface antigens effectively makes the M subtype “invisible” to the immune system.
Fortunately, drugs called epigenetic inhibitors can release the PRC2 lock on antigen-presenting genes. The researchers tested drugs that block two PRC2 subunits, EZH2 and EED, and found they restored MHC-I expression and enhanced the efficacy of chemotherapy in a mouse tumor model.
Adding these inhibitors, which are being tested clinically in other cancers, to standard chemotherapy in the treatment of specific TNBC subtypes “may be a way to get the immune system back in the fight,” Lehmann said.
Lehmann was the paper’s co-first author with the University of Miami’s Antonio Colaprico, PhD. Other VUMC contributors were Hanbing An, PhD, Jamaal James, PhD, Justin Balko, PhD, Paula Gonzalez Ericsson, MD, and Melinda Sanders, MD.
The research was supported by the U.S. Department of Defense Breast Cancer Research Program, the Susan G. Komen breast cancer organization, and NIH grants CA200987, CA158472, CA068485, CA098131 and CA210954.
