TRANCE- and CD40 ligand-matured dendritic cells reveal MHC class I-restricted T cells specific for autologous tumor in late-stage ovarian cancer patients.
OBJECTIVE
The use of mature dendritic cells (DCs) presenting tumor-associated antigens (TAAs) to trigger tumor-specific T cells in vivo or in vitro represents a promising approach for cancer immunotherapy. We hypothesized that tumor antigens, mostly unidentified, are present on ovarian tumor cells and that mature DCs could be used to generate tumor-specific responses in unprimed patients. We also sought to measure preexisting antitumor immunity in patients with advanced ovarian cancer.


METHODS
Autologous DCs from 10 patients with ovarian cancer were pulsed with killed autologous primary tumors as a source of TAAs. DCs were then cultured in the presence of tumor necrosis factor alpha + TRANCE (tumor necrosis factor-related activation-induced cytokine) to induce maturation. Mature TAA-pulsed DCs were used in vitro to stimulate tumor-specific peripheral blood T cells.


RESULTS
TRANCE and CD40 ligand were effective at maturing DCs. T-cell lines were generated in vitro that were capable of secreting IFN-gamma in response to autologous tumor. These tumor-specific T cells were MHC class I restricted. The frequency of tumor-specific T cells in uncultured cells from malignant ascites fluid and peripheral blood was measured in the same patients.


CONCLUSIONS
IFN-gamma-secreting tumor-specific T cells were demonstrated at baseline in uncultured T cells from some unvaccinated ovarian cancer patients; however, the T cells could not kill autologous tumor. These data demonstrate that mature DCs presenting tumor antigens from engulfed autologous tumors can be used to augment antitumor immunity in vitro in patients with epithelial ovarian cancer. The results support the feasibility of therapeutic vaccination of ovarian cancer patients.
Schlienger
Katia
K
Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Chu
Christina S
CS
Woo
Edward Y
EY
Rivers
Patricia M
PM
Toll
Alanna J
AJ
Hudson
Brian
B
Maus
Marcela V
MV
Riley
James L
JL
Choi
Yongwon
Y
Coukos
George
G
Kaiser
Larry R
LR
Rubin
Stephen C
SC
Levine
Bruce L
BL
Carroll
Richard G
RG
June
Carl H
CH
D000328:Adult; D000368:Aged; D017209:Apoptosis; D023201:CD40 Ligand / Q000378:metabolism*; D019496:Cancer Vaccines; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005805:Genes, MHC Class I / Q000235:genetics*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism*; D010587:Phagocytosis; D010641:Phenotype; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013601:T-Lymphocytes / Q000378:metabolism*; D014466:Ultraviolet Rays
D019496:Cancer Vaccines; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D023201:CD40 Ligand; D007371:Interferon-gamma