Enhanced tumor responses to dendritic cells in the absence of CD8-positive cells.
Wild-type mice immunized with MART-1 melanoma Ag-engineered dendritic cells (DC) generate strong Ag-specific immunity that has an absolute requirement for both CD8(+) and CD4(+) T cells. DC administration to CD8 alpha knockout mice displayed unexpectedly enhanced levels of protection to tumor challenge despite this deficiency in CD8(+) T cells and the inability to mount MHC class I-restricted immune responses. This model has the following features: 1) antitumor protection is Ag independent; 2) had an absolute requirement for CD4(+) and NK1.1(+) cells; 3) CD4(+) splenocytes are responsible for cytokine production; 4) lytic cells in microcytotoxicity assays express NK, but lack T cell markers (NK1.1(+) alpha beta TCR(-) CD3(-)); and 5) the lytic phenotype can be transferred to naive CD8 alpha knockout mice by NK1.1(+) splenocytes. Elucidation of the signaling events that activate these effective cytotoxic cells and the putative suppressive mechanisms in a wild-type environment may provide means to enhance the clinical activity of DC-based approaches.
Ribas
Antoni
A
Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, CA 90095, USA. aribas@mednet.ucla.edu
Wargo
Jennifer A
JA
Comin-Anduix
Begonya
B
Sanetti
Shelley
S
Schumacher
Lana Y
LY
McLean
Colin
C
Dissette
Vivian B
VB
Glaspy
John A
JA
McBride
William H
WH
Butterfield
Lisa H
LH
Economou
James S
JS
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000941:Antigens / Q000096:biosynthesis; D000950:Antigens, Ly; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation* / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D058965:MART-1 Antigen; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008912:Minor Histocompatibility Loci / Q000235:genetics; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation
D000941:Antigens; D000950:Antigens, Ly; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D016827:CD8 Antigens; C431698:CD8alpha antigen; D018984:Epitopes, T-Lymphocyte; C527203:KLRB1 protein, human; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009363:Neoplasm Proteins; D011506:Proteins; D007371:Interferon-gamma