Apoptotic, but not necrotic, tumor cell vaccines induce a potent immune response in vivo.
Prophylactic tumor vaccination against subsequent tumor challenge depends on effective cross-priming in vivo. Professional APCs process tumor antigens from whole tumor cells and present them to CD4(+) and CD8(+) T cells. Data suggest that dendritic cells process antigens more efficiently from necrotic cells than from apoptotic cells in vitro. We compared the effect of apoptosis vs. necrosis in vivo using different tumor models (CT26, RENCA, B16 and CT26-HA). Apoptosis was induced by gamma-irradiation prior to injection and verified in vivo. Apoptotic CT26-HA, CT26-wt or RENCA prevented tumor outgrowth in 100%, 75% and 100%, respectively, of mice for more than 30 days after challenge. In contrast, injection of necrotic tumor cells led to protection of no more than 0-30%. Prolonged tumor-free survival was also observed in mice after vaccination with irradiated B16 cells. In vivo protection experiments correlated very well with in vitro cytotoxicity assays. Immunohistochemical analysis of the vaccine site showed a strong CD4(+) and CD8(+) T-cell response after injection of apoptotic cells, which was accompanied by the presence of dendritic cells. In contrast, necrotic cell vaccines attracted a strong local macrophage response. Our data clearly demonstrate that only apoptotic tumor cell vaccines induce a potent antitumor immune response.
Scheffer
Stephan R
SR
Department of Gastroenterology, Medizinische Hochschule Hannover, Hannover, Germany.
Nave
Heike
H
Korangy
Firouzeh
F
Schlote
Karola
K
Pabst
Reinhard
R
Jaffee
Elizabeth M
EM
Manns
Michael P
MP
Greten
Tim F
TF
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D020287:In Situ Nick-End Labeling; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010587:Phagocytosis / Q000276:immunology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects
D017304:Annexin A5; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D019707:Receptors, Chemokine