Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells.
If irradiated tumor cells could be rendered immunogenic, they would provide a safe, broad, and patient-specific array of antigens for immunotherapies. Prior approaches have emphasized genetic transduction of live tumor cells to express cytokines, costimulators, and surrogate foreign antigens. We asked if immunity could be achieved by delivering irradiated, major histocompatibility complex-negative plasmacytoma cells to maturing mouse dendritic cells (DCs) within lymphoid organs. Tumor cells injected intravenously (i.v.) were captured by splenic DCs, whereas subcutaneous (s.c.) injection led only to weak uptake in lymph node or spleen. The natural killer T (NKT) cells mobilizing glycolipid alpha-galactosyl ceramide, used to mature splenic DCs, served as an effective adjuvant to induce protective immunity. This adjuvant function was mimicked by a combination of poly IC and agonistic alphaCD40 antibody. The adjuvant glycolipid had to be coadministered with tumor cells i.v. rather than s.c. Specific resistance was generated both to a plasmacytoma and lymphoma. The resistance afforded by a single vaccination lasted >2 mo and required both CD4+ and CD8+ T cells. Mature tumor capturing DCs stimulated the differentiation of P1A tumor antigen-specific, CD8+ T cells and uniquely transferred tumor resistance to naive mice. Therefore, the access of dying tumor cells to DCs that are maturing to activated NKT cells efficiently induces long-lived adaptive resistance.
Liu
Kang
K
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA.
Idoyaga
Juliana
J
Charalambous
Anna
A
Fujii
Shin-Ichiro
S
Bonito
Anthony
A
Mordoh
Jose
J
Wainstok
Rosa
R
Bai
Xue-Feng
XF
Liu
Yang
Y
Steinman
Ralph M
RM
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000528:radiation effects; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005720:Gamma Rays; D016233:Immunotherapy, Active / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D010954:Plasmacytoma / Q000276:immunology* / Q000628:therapy; D013154:Spleen / Q000276:immunology
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C076546:tumor rejection antigen P815A, mouse