HDAC inhibition potentiates immunotherapy in triple negative breast cancer
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Manuela Terranova-Barberio1, Scott Thomas1, Niwa Ali2, Nela Pawlowska1, Jeenah Park1, Gregor Krings3, Michael D. Rosenblum2, Alfredo Budillon4 and Pamela N. Munster1
1Division of Hematology and Oncology, University of California, San Francisco, California, USA
2Department of Dermatology, University of California, San Francisco, California, USA
3Division of Pathology, University of California, San Francisco, California, USA
4Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
Pamela N. Munster, email: [email protected]
Keywords: HDAC inhibitor; immunotherapy; checkpoint inhibitor; triple negative breast cancer; epigenetics modulators
Received: September 19, 2017 Accepted: November 26, 2017 Published: December 12, 2017
Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC.
Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy. Tumor cells were co-cultured with human peripheral blood mononuclear cells (PBMCs) and flow cytometric immunophenotyping was performed to define the role of epigenetic priming in promoting tumor antigen presentation and immune cell activation. We found that HDACi up-regulate PD-L1 mRNA and protein expression in a time-dependent manner in TNBC cells, but not in hormone responsive cells. Focusing on TNBC, HDACi up-regulated PD-L1 and HLA-DR on tumor cells when co-cultured with PBMCs and down-regulated CD4+ Foxp3+ Treg in vitro. HDACi significantly enhanced the in vivo response to PD-1/CTLA-4 blockade in the triple-negative 4T1 breast cancer mouse model, the only currently available experimental system with functional resemblance to human TNBC. This resulted in a significant decrease in tumor growth and increased survival, associated with increased T cell tumor infiltration and a reduction in CD4+ Foxp3+ T cells in the tumor microenvironment. Overall, our results suggest a novel role for HDAC inhibition in combination with immune checkpoint inhibitors and identify a promising therapeutic strategy, supporting its further clinical evaluation for TNBC treatment.
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