title: DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer.
abstract: Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer.
authors.affiliation: Department of Surgery, Virginia Commonwealth University, Richmond, VA, USA.|Massey Cancer Center, School of Medicine, Virginia Commonwealth University, West Hospital 7-402, 1200 East Broad Street, PO Box 980011, Richmond, VA, 23298-0011, USA.
authors.forename: Krista P
authors.initials: KP
authors.lastname: Terracina
authors.affiliation: Department of Surgery, Virginia Commonwealth University, Richmond, VA, USA.|Massey Cancer Center, School of Medicine, Virginia Commonwealth University, West Hospital 7-402, 1200 East Broad Street, PO Box 980011, Richmond, VA, 23298-0011, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Graham
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Payne
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.|Massey Cancer Center, School of Medicine, Virginia Commonwealth University, West Hospital 7-402, 1200 East Broad Street, PO Box 980011, Richmond, VA, 23298-0011, USA.
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.affiliation: Massey Cancer Center, School of Medicine, Virginia Commonwealth University, West Hospital 7-402, 1200 East Broad Street, PO Box 980011, Richmond, VA, 23298-0011, USA.
authors.forename: Annabel
authors.initials: A
authors.lastname: Baek
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.|Massey Cancer Center, School of Medicine, Virginia Commonwealth University, West Hospital 7-402, 1200 East Broad Street, PO Box 980011, Richmond, VA, 23298-0011, USA.
authors.forename: Sheela R
authors.initials: SR
authors.lastname: Damle
authors.affiliation: Department of Surgery, Virginia Commonwealth University, Richmond, VA, USA. hdbear@vcu.edu.|Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA. hdbear@vcu.edu.|Massey Cancer Center, School of Medicine, Virginia Commonwealth University, West Hospital 7-402, 1200 East Broad Street, PO Box 980011, Richmond, VA, 23298-0011, USA. hdbear@vcu.edu.
authors.forename: Harry D
authors.initials: HD
authors.lastname: Bear
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine
keywords: Decitabine; Epigenetic; Immunotherapy; Myeloid derived suppressor cells; T lymphocytes