title: External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing.
abstract: Local radiation is an established therapy for human tumors. Radiation also has been shown to alter the phenotype of target tissue, including gene products that may make tumor cells more susceptible to T-cell-mediated immune attack. We demonstrate a biological synergy between local radiation of tumor and active vaccine therapy. The model used consisted of mice transgenic for human carcinoembryonic antigen (CEA) and a murine carcinoma cell line transfected with CEA. The vaccine regimen consisted of a prime and boost strategy using vaccinia and avipox recombinants expressing CEA and three T-cell costimulatory molecules. One dose of 8-Gy radiation to tumor induced up-regulation of the death receptor Fas in situ for up to 11 days. However, neither radiation at this dose nor vaccine therapy was capable of inhibiting growth of 8-day established tumor. When vaccine therapy and local radiation of tumor were used in combination, dramatic and significant cures were achieved. This was mediated by the engagement of the Fas/Fas ligand pathway because Ag-bearing tumor cells expressing dominant-negative Fas were not susceptible to this combination therapy. Following the combination of vaccine and local radiation, tumors demonstrated a massive infiltration of T cells not seen with either modality alone. Mice cured of tumors demonstrated CD4(+) and CD8(+) T-cell responses specific for CEA but also revealed the induction of high levels of T-cell responses to two other antigens (gp70 and p53) overexpressed in tumor, indicating the presence of a consequential antigen cascade. Thus, these studies demonstrate a new paradigm for the use of local tumor irradiation in combination with active specific vaccine therapy to elicit durable antitumor responses of established tumors.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mala
authors.initials: M
authors.lastname: Chakraborty
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.forename: C Norman
authors.initials: CN
authors.lastname: Coleman
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D053222:Fas Ligand Protein; D005260:Female; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology / Q000528:radiation effects; D019014:fas Receptor / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor