title: CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes.
abstract: Cancer-specific splice variants gain significant interest as they generate neo-antigens that could be targeted by immune cells. CD20, a membrane antigen broadly expressed in mature B cells and in B cell lymphomas, is subject to an alternative splicing named D393-CD20 leading to loss of membrane expression of the spliced isoform. D393-CD20 expression is detectable in transformed B cells and upregulated in various lymphoma B cells. In this study, we show that D393-CD20 is translated in malignant B cells and that D393-CD20 specific CD4 T cells producing IFN-γ are present in B-cell lymphoma patients. Then, we have investigated whether the 20mer D393-CD20 peptide spanning the splicing site might be targeted by the immune system and we have shown that D393-CD20-specific CD4 Th1 clones could directly recognize malignant B cell lines and kill autologous lymphoma B cells indicating that D393-CD20-derived epitopes are naturally processed and presented on tumor cells. Finally, D393-CD20 peptide-based vaccination induced specific CD8 and CD4 T cell responses in HLA-humanized transgenic mice suggesting the presentation of D393-CD20 derived peptides on both HLA Class-I and -II. These findings support further investigations on the potential use of D393-CD20 directed specific immunotherapy in B cell malignancies.
authors.affiliation: INSERM UMR1098, F25020 Besançon cedex, France; Université de Franche-Comté, F25020 Besançon cedex, France; EFS Bourgogne Franche-Comté, F25020 Besançon cedex, France.
authors.forename: Charline
authors.initials: C
authors.lastname: Vauchy
authors.forename: Clementine
authors.initials: C
authors.lastname: Gamonet
authors.forename: Christophe
authors.initials: C
authors.lastname: Ferrand
authors.forename: Etienne
authors.initials: E
authors.lastname: Daguindau
authors.forename: Jeanne
authors.initials: J
authors.lastname: Galaine
authors.forename: Laurent
authors.initials: L
authors.lastname: Beziaud
authors.forename: Adrien
authors.initials: A
authors.lastname: Chauchet
authors.forename: Carole J
authors.initials: CJ
authors.lastname: Henry Dunand
authors.forename: Marina
authors.initials: M
authors.lastname: Deschamps
authors.forename: Pierre Simon
authors.initials: PS
authors.lastname: Rohrlich
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.forename: Olivier
authors.initials: O
authors.lastname: Adotevi
authors.forename: Yann
authors.initials: Y
authors.lastname: Godet
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D018951:Antigens, CD20 / Q000235:genetics* / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007114:Immunization; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D020033:Protein Isoforms
keywords: B-cell lymphoma; CD20 antigen; CD4 T cells; immunotherapy; splicing