Breast Cancer Discovery
April 29, 2022
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, 2021, 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 at 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.
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.
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 of 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.
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.
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.