title: Apoptosis-dependent subversion of the T-lymphocyte epitope hierarchy in lymphoma cells.
abstract: Tumor cells undergoing programmed death are an attractive source of tumor-associated antigens, and evidences are available for their therapeutic efficacy in vivo when used either alone or in association with dendritic cells. However, little is known about the specificity of the immune response induced by such antigen formulation. Indeed, activation of specific proteases during apoptosis may influence the cytoplasmic degradation of proteins and the generation of CTL epitopes. We show here that on injection of C57BL/6 mice either with RMA lymphoma cells induced to apoptosis or bone marrow-derived dendritic cells pulsed with apoptotic RMA cells, a specific and protective CTL response is induced, which, however, is not directed against the immunodominant CTL epitope gag(85-93). Lack of in vivo expansion of gag(85-93)-specific CTL in vaccinated mice is attributable to the apoptosis-dependent loss of gag(85-93) in dying tumor cells. Indeed, we found loss of gag(85-93) in RMA, MBL-2, and EL-4G+ lymphoma cells, which share gag(85-93) as an immunodominant CTL epitope, induced to apoptosis by UV irradiation, mitomycin C, doxorubicin, or daunorubicin. This phenomenon appears to be caspase-dependent, because caspase inhibition by N-benzyloxycarbonyl-Val-Ala-asp-fluoromethylketone prevents apoptosis of lymphoma cells and loss of gag(85-93). Therefore, subversion of the epitope hierarchy in apoptotic tumor cells might be relevant in the induction of tumor-specific T-lymphocyte responses.
authors.affiliation: Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico H San Raffaele, Milan Italy, 20132.
authors.forename: Paola
authors.initials: P
authors.lastname: Castiglioni
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martin-Fontecha
authors.forename: Gabriella
authors.initials: G
authors.lastname: Milan
authors.forename: Valentina
authors.initials: V
authors.lastname: Tomajer
authors.forename: Fulvio
authors.initials: F
authors.lastname: Magni
authors.forename: Jakob
authors.initials: J
authors.lastname: Michaelsson
authors.forename: Claudio
authors.initials: C
authors.lastname: Rugarli
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.forename: Matteo
authors.initials: M
authors.lastname: Bellone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D020169:Caspases / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015683:Gene Products, gag / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011925:Rauscher Virus; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013945:Thymoma / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D016056:Immunodominant Epitopes; D020169:Caspases