title: Effect of adenovirus-mediated heat shock protein expression and oncolysis in combination with low-dose cyclophosphamide treatment on antitumor immune responses.
abstract: Heat shock proteins such as gp96 have the ability to chaperone peptides and activate antigen-presenting cells. In this study, we tested whether adenovirus-mediated overexpression of secreted or membrane-associated forms of gp96 in tumor cells would stimulate an antitumor immune response. Studies were carried out in C57Bl/6 mice bearing aggressively growing s.c. tumors derived from syngeneic TC-1 cells, a cell line that expresses HPV16 E6 and E7 proteins. We found that secreted gp96 can induce protective and therapeutic antitumor immune responses. Our data also indicate that the antitumor effect of sgp96 expression seems to be limited by the induction of suppressive regulatory T cells (Treg). TC-1 tumor transplantation increased the number of splenic and tumor-infiltrating Tregs. Importantly, treatment of mice with low-dose cyclophosphamide decreased the number of Tregs and enhanced the immunostimulatory effect of sgp96 expression. We also tested whether an oncolytic vector (Ad.IR-E1A/TRAIL), that is able to induce tumor cell apoptosis and, potentially, release cryptic tumor epitopes in immunogenic form, could stimulate antitumor immune responses. Although tumor cells infected ex vivo with Ad.IR-E1A/TRAIL had no antitumor effect when used as a vaccine alone, the additional treatment with low-dose cyclophosphamide resulted in the elimination of pre-established tumors. This study gives a rationale for testing approaches that suppress Tregs in combination with oncolytic or immunostimulatory vectors.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Nelson C
authors.initials: NC
authors.lastname: Di Paolo
authors.forename: Sebastian
authors.initials: S
authors.lastname: Tuve
authors.forename: Shaoheng
authors.initials: S
authors.lastname: Ni
authors.forename: Karl Erik
authors.initials: KE
authors.lastname: Hellström
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Hellström
authors.forename: André
authors.initials: A
authors.lastname: Lieber
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D019496:Cancer Vaccines; D003520:Cyclophosphamide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D052162:Human papillomavirus 16; D006801:Humans; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D009856:Oncogene Proteins, Viral; D050130:Oncolytic Virotherapy; D012097:Repressor Proteins; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000276:immunology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C053387:endoplasmin; D003520:Cyclophosphamide