TNF-alpha coupled to membrane of apoptotic cells favors the cross-priming to melanoma antigens.
The cross-presentation of Ags derived from apoptotic cell processing contributes to peripheral tolerance. Environmental signals possibly modify this default outcome, favoring cross-priming. In this study, we anchored via a biotin-avidin-biotin bridge soluble TNF-alpha to the membrane of apoptotic melanoma cells and studied in vivo and in vitro the interaction with Ag-presenting phagocytes. TNF-alpha-coated apoptotic melanoma cells injected s.c. had a faster and more efficient access to draining lymph nodes, with cross-priming of melanoma-specific CTLs and delayed outgrowth of melanomas in all treated animals. Twenty percent of the animals, in the absence of further adjuvant, did not develop the tumor. Immature dendritic cells challenged with TNF-alpha-coated apoptotic melanoma cells secreted proinflammatory cytokines in an autocrine/paracrine fashion, efficiently matured, as assessed functionally and by flow cytometry and cross-presented with enhanced efficiency melanoma Ags to MHC class I- and II-restricted T cells. The results indicate that TNF-alpha targeted to apoptotic membranes, at concentrations that can be safely reached in growing tumors without undue systemic toxicity, influences the outcome of the disposal of dying cells and enhances tumor immunogenicity.
Zimmermann
Valérie S
VS
Cancer Immunotherapy and Gene Therapy Program, H San Raffaele Scientific Institute and San Raffaele Vita-Salute University, Milano, Italy.
Bondanza
Attilio
A
Monno
Antonella
A
Rovere-Querini
Patrizia
P
Corti
Angelo
A
Manfredi
Angelo A
AA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000378:metabolism* / Q000502:physiology
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D014409:Tumor Necrosis Factor-alpha