title: Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy.
abstract: CD8(+) CTL play important roles against malignancy in both active and passive immunotherapy. Nonetheless, the success of antitumor CTL responses may be improved by additional therapeutic modalities. Radiotherapy, which has a long-standing use in treating neoplastic disease, has been found to induce unique biologic alterations in cancer cells affecting Fas gene expression, which, consequently, may influence the overall lytic efficiency of CTL. Here, in a mouse adenocarcinoma cell model, we examined whether exposure of these tumor cells to sublethal doses of irradiation 1) enhances Fas expression, leading to more efficient CTL killing via Fas-dependent mechanisms in vitro; and 2) improves antitumor activity in vivo by adoptive transfer of these Ag-specific CTL. Treatment of carcinoembryonic Ag-expressing MC38 adenocarcinoma cells with irradiation (20 Gy) in vitro enhanced Fas expression at molecular, phenotypic, and functional levels. Furthermore, irradiation sensitized these targets to Ag-specific CTL killing via the Fas/Fas ligand pathway. We examined the effect of localized irradiation of s.c. growing tumors on the efficiency of CTL adoptive immunotherapy. Irradiation caused up-regulation of Fas by these tumor cells in situ, based on immunohistochemistry. Moreover, localized irradiation of the tumor significantly potentiated tumor rejection by these carcinoembryonic Ag-specific CTL. Overall, these results showed for the first time that 1) regulation of the Fas pathway in tumor cells by irradiation plays an important role in their sensitization to Ag-specific CTL; and 2) a combination regimen of tumor-targeted irradiation and CTL promotes more effective antitumor responses in vivo, which may have implications for the combination of immunotherapy and radiation therapy.
authors.affiliation: Laboratory of Tumor Immunology and Biology and Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mala
authors.initials: M
authors.lastname: Chakraborty
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.forename: Tamalee
authors.initials: T
authors.lastname: Scott
authors.forename: C Norman
authors.initials: CN
authors.lastname: Coleman
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology / Q000528:radiation effects; D002455:Cell Division / Q000276:immunology / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D003602:Cytotoxicity, Immunologic / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000528:radiation effects; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000528:radiation effects; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000528:radiation effects* / Q000637:transplantation*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000473:pathology / Q000528:radiation effects / Q000637:transplantation; D015854:Up-Regulation / Q000276:immunology* / Q000528:radiation effects; D019014:fas Receptor / Q000096:biosynthesis* / Q000502:physiology / Q000528:radiation effects
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1