title: Local administration of granulocyte macrophage colony-stimulating factor induces local accumulation of dendritic cells and antigen-specific CD8+ T cells and enhances dendritic cell cross-presentation.
abstract: Immunotherapy has emerged as a promising treatment strategy for the control of HPV-associated malignancies. Various therapeutic HPV vaccines have elicited potent antigen-specific CD8+ T cell mediated antitumor immune responses in preclinical models and are currently being tested in several clinical trials. Recent evidence indicates the importance of local immune activation, and higher number of immune cells in the site of lesion correlates with positive prognosis. Granulocyte macrophage colony-stimulating factor (GMCSF) has been reported to posses the ability to induce migration of antigen presentation cells and CD8+ T cells. Therefore, in the current study, we employ a combination of systemic therapeutic HPV DNA vaccination with local GMCSF application in the TC-1 tumor model. We show that intramuscular vaccination with CRT/E7 DNA followed by GMCSF intravaginal administration effectively controls cervicovaginal TC-1 tumors in mice. Furthermore, we observe an increase in the accumulation of E7-specific CD8+ T cells and dendritic cells in vaginal tumors following the combination treatment. In addition, we show that GMCSF induces activation and maturation in dendritic cells and promotes antigen cross-presentation. Our results support the clinical translation of the combination treatment of systemic therapeutic vaccination followed by local GMCSF administration as an effective strategy for tumor treatment.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Department of Obstetrics and Gynecology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea.
authors.forename: Sung-Jong
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Pharmacy School of Fudan University, Shanghai, China; Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China; Department of Pharmacology and Toxicology, Shanghai Institute of Planned Parenthood Research, Shanghai, China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Yang
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
authors.forename: Chih-Ping
authors.initials: CP
authors.lastname: Mao
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jeang
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Departments of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Departments of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: chung2@jhmi.edu.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000276:immunology; D007167:Immunotherapy; D007273:Injections, Intramuscular; D051379:Mice; D008810:Mice, Inbred C57BL; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D002583:Uterine Cervical Neoplasms / Q000628:therapy; D014611:Vaccination; D014625:Vaginal Neoplasms / Q000628:therapy
chemical_list: D019496:Cancer Vaccines; D053918:Papillomavirus Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: CRT/E7; Dendritic cell; GM-CSF; Immunotherapy