Therapeutic combinations to alter the immunosuppressive, solid tumor microenvironment (TME), such as in breast cancer, are essential to improve responses to immune checkpoint inhibitors (ICIs), a new form of cancer immunotherapy. Entinostat, an oral histone deacetylase inhibitor, has been shown to improve responses to ICIs in various tumor models with an immunosuppressive TME. However, the precise alterations to the TME induced by entinostat remained unknown.
 
Now, a new study published in Cancer Immunology Research suggests that entinostat induced changes to multiple myeloid cell types, reduced immunosuppression, increased antitumor immune responses, and improved sensitivity to ICIs.
 
“We are excited to share our paper describing our work showing breast tumor sensitization to immune checkpoint inhibition using epigenetic modulation” says Evanthia Roussos Torres, MD, PhD, member of the USC Norris Tumor Microenvironment Program and Assistant Professor of Medicine at the Keck School of Medicine. “This work will aid in the development of novel strategies to improve response rates to immunotherapy of breast cancer.”
 
For this study Dr. Roussos Torres employed single-cell RNA sequencing on HER2-overexpressing breast tumors from mice treated with entinostat and ICIs to fully characterize changes across multiple cell types within the TME. This analysis demonstrated that treatment with entinostat induced a shift from a protumor to an antitumor TME signature, characterized predominantly by changes in myeloid cells in which suppressive signaling pathways were altered. In addition, tumor- associated macrophages were epigenetically reprogrammed from a protumor phenotype towards an antitumor phenotype. The study concluded that the use of entinostat could ultimately broaden the population of breast cancer patients that could benefit from ICIs.
 
About this study:
 
In addition to Dr. Evanthia Roussos Torres, other contributors from the USC Norris Comprehensive Cancer Center and the Keck School of Medicine include Drs. Julie K. Jang, Sofi Castanon, Aaron G. Baugh, Edgar Gonzalez, Valerie H. Narumi, Sathish Kumar Ganesan, and Min Yu. Other major contributions were made from Johns Hopkins University School of Medicine, University of Miami Miller School of Medicine, Sidney Kimmel Comprehensive Cancer Center, College of Medicine and Health at the University College Cork, University of Maryland Medical Center, and the University of Maryland Marlene and Stewart Greenebaum Cancer Center.