title: Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells.
abstract: Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25(+) NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25(+) NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy.
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; The Wistar Institute, Philadelphia, Pennsylvania, USA kpayne@wistar.org.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Payne
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Keim
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
authors.forename: Laura
authors.initials: L
authors.lastname: Graham
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
authors.forename: Michael O
authors.initials: MO
authors.lastname: Idowu
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
authors.forename: Wen
authors.initials: W
authors.lastname: Wan
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; and.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Toor
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
authors.forename: Harry D
authors.initials: HD
authors.lastname: Bear
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; masoud.manjili@vcuhealth.org.
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008822:Mice, Transgenic; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
keywords: adoptive immunotherapy; breast cancer; dormancy; escape; relapse