title: Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors.
abstract: OBJECTIVE
  Radiotherapy kills cancer cells by causing DNA damage, and stimulates a systemic antitumor immune response by releasing tumor antigen and endogenous adjuvant within the tumor microenvironment. However, radiotherapy also induces the recruitment of immunosuppressive myeloid cells, which can interfere with the antitumor immune responses elicited by apoptotic tumor cells. We hypothesized that local delivery of vaccine following radiotherapy will lead to the priming of antigen-specific CTL immune responses and render immunosuppressive myeloid cells susceptible to killing by the activated CTLs.
  
  
  METHODS
  Using several antigenic systems, we tested whether intratumoral injection of antigenic peptide/protein in irradiated tumors would be able to prime CTLs as well as load myeloid cells with antigen, rendering them susceptible to antigen-specific CTL killing.
  
  
  RESULTS
  We show that by combining radiotherapy and targeted antigenic peptide delivery to the tumor, the adjuvant effect generated by radiotherapy itself was sufficient to elicit the priming and expansion of antigen-specific CTLs, through the type I IFN-dependent pathway, leading to synergistic therapeutic antitumor effects compared with either treatment alone. In addition, using two different types of transgenic mice, we demonstrated that CTL-mediated killing of stromal cells in tumors by our approach is important for tumor control. Finally, we confirmed the efficacy of this approach in our preclinical model using two clinically tested therapeutic human papilloma virus (HPV) vaccines.
  
  
  CONCLUSIONS
  These data serve as an important foundation for the future clinical translation of radiotherapy combined with a clinically tested therapeutic HPV vaccine for the control of HPV-associated cancers.
authors.affiliation: Authors' Affiliations: Departments of Pathology, Obstetrics and Gynecology, Molecular Microbiology and Immunology, Oncology, and Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions; Department of Biostatistics and Bioinformatics, Sidney Kimmel Cancer Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland; Departments of Obstetrics and Gynecology, Kunming Medical University, Yunnan, China; Nephrology, Chang-Gung Memorial Hospital, Gueishan; Department of Obstetrics and Gynecology, Tri-Service General Hospital, Taipei, Taiwan; and Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Chao-Yi
authors.initials: CY
authors.lastname: Wu
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Yang
authors.forename: Huang-Yu
authors.initials: HY
authors.lastname: Yang
authors.forename: Jayne
authors.initials: J
authors.lastname: Knoff
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Lin
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: Sara I
authors.initials: SI
authors.lastname: Pai
authors.forename: Richard B S
authors.initials: RB
authors.lastname: Roden
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D053918:Papillomavirus Vaccines / Q000276:immunology; D011878:Radiotherapy; D017154:Stromal Cells / Q000276:immunology / Q000528:radiation effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology* / Q000528:radiation effects; D059016:Tumor Microenvironment / Q000276:immunology* / Q000528:radiation effects
chemical_list: D019496:Cancer Vaccines; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16