title: Inhibition of phosphatidylserine recognition heightens the immunogenicity of irradiated lymphoma cells in vivo.
abstract: Strategies to enhance the immunogenicity of tumors are urgently needed. Although vaccination with irradiated dying lymphoma cells recruits a tumor-specific immune response, its efficiency as immunogen is poor. Annexin V (AxV) binds with high affinity to phosphatidylserine on the surface of apoptotic and necrotic cells and thereby impairs their uptake by macrophages. Here, we report that AxV preferentially targets irradiated lymphoma cells to CD8+ dendritic cells for in vivo clearance, elicits the release of proinflammatory cytokines and dramatically enhances the protection elicited against the tumor. The response was endowed with both memory, because protected animals rejected living lymphoma cells after 72 d, and specificity, because vaccinated animals failed to reject unrelated neoplasms. Finally, AxV-coupled irradiated cells induced the regression of growing tumors. These data indicate that endogenous adjuvants that bind to dying tumor cells can be exploited to target tumors for immune rejection.
authors.affiliation: Clinical Immunology Unit, Cancer Immunotherapy and Gene Therapy Program, H. San Raffaele Institute, DIBIT 3A1, via Olgettina 58, 20132 Milano, Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.forename: Valérie S
authors.initials: VS
authors.lastname: Zimmermann
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
authors.forename: Javier
authors.initials: J
authors.lastname: Turnay
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Dumitriu
authors.forename: Christian M
authors.initials: CM
authors.lastname: Stach
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.forename: Udo S
authors.initials: US
authors.lastname: Gaipl
authors.forename: Wolf
authors.initials: W
authors.lastname: Bertling
authors.forename: Ernst
authors.initials: E
authors.lastname: Pöschl
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Kalden
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Manfredi
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007114:Immunization; D008223:Lymphoma / Q000276:immunology* / Q000628:therapy*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
chemical_list: D017304:Annexin A5; C498708:Ptdsr protein, mouse; D011956:Receptors, Cell Surface; C408123:phosphatidylserine receptor