title: Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy.
abstract: BACKGROUND
  Immunotherapies targeting cellular immunity are currently approved for treatment of melanoma, renal cell carcinoma, and prostate cancer. Studies on the immunogenicity and immune responsiveness of pediatric tumors are limited, therefore, it remains unclear to what extent T-cell-based immunotherapy holds promise for pediatric solid tumors.
  
  
  METHODS
  A new rhabdomyosarcoma cell line (M3-9-M) was derived from an embryonal rhabdomyosarcoma (ERMS) occurring in a C57BL/6 mouse transgenic for hepatocyte growth factor and heterozygous for mutated p53. Primary tumors and metastases derived from M3-9-M were studied for similarities to human ERMS, and for immunogenicity and immune responsiveness.
  
  
  RESULTS
  Primary and metastatic tumors develop after orthotopic injection of M3-9-M into immunocompetent C57BL/6 mice, which mirror human ERMS with regard to histology, gene expression, and metastatic behavior. Whole cell vaccination using irradiated M3-9-M cells or M3-9-M-pulsed dendritic cells (DC)-induced tumor-specific T-cell responses that prevent tumor growth following low-dose tumor injection, and slow tumor growth following higher doses. Administration of anti-CD25 moAbs to deplete CD4(+)CD25(+)FOXP3(+) regulatory T cells prior to tumor vaccination enhanced the potency of the ERMS tumor vaccine. Adoptive immunotherapy with M3-9-M primed T cells plus DC-based vaccination resulted in complete eradication of day 10 M3-9-M derived tumors.
  
  
  CONCLUSIONS
  M3-9-M derived murine ERMS is immunogenic and immunoresponsive; regulatory T cells contribute to immune evasion by murine rhabdomyosarcoma. Adoptive immunotherapy with DC vaccination can eradicate low tumor burdens. Future work will seek to identify the tumor-associated antigens that mediate protective and therapeutic immunity in this model.
authors.affiliation: Immunology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Meadors
authors.forename: Yonghzi
authors.initials: Y
authors.lastname: Cui
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Chen
authors.forename: Young K
authors.initials: YK
authors.lastname: Song
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: Rimas J
authors.initials: RJ
authors.lastname: Orentas
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D012208:Rhabdomyosarcoma / Q000276:immunology* / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines