Type-1 polarized dendritic cells loaded with apoptotic prostate cancer cells are potent inducers of CD8(+) T cells against prostate cancer cells and defined prostate cancer-specific epitopes.
BACKGROUND
In order to develop improved vaccines for patients with recurrent prostate cancer (PCa), we tested the feasibility of using type-1 polarized dendritic cells (αDC1s) to cross-present antigens from allogeneic PCa cells and to induce functional CD8(+) T cell responses against PCa cells and against defined MHC class I-restricted PCa-relevant epitopes.


METHODS
Monocyte-derived DCs from PCa patients were matured using the "standard" cytokine cocktail (IL-1β/TNFα/IL-6/PGE₂) or using the αDC1-polarizing cocktail (IL-1β/TNFα/IFNα/IFNγ/poly-I:C), loaded with UV-irradiated LNCaP cells, and used to sensitize autologous CD8(+) T cells.


RESULTS
αDC1s from PCa patients secreted 10-30 times higher levels of IL-12p70 than sDCs. Importantly this elevated capacity for IL-12p70 secretion was not inhibited by loading with apoptotic tumor cells. Compared to standard DCs, αDC1s induced higher numbers of CD8(+) T cells capable of recognizing both the original PCa cells as well as another PCa cell line, DU145, in MHC class I-restricted fashion. Furthermore, αDC1s induced higher numbers of CD8(+) T cells recognizing defined PCa-specific class I-restricted peptide epitopes of prostate-specific antigen and prostatic acid phosphatase: PAP(135-143) (average 49-fold higher), PAP(112-120) (average 24-fold), PSA(141-150) (average 5.5-fold), and PSA(146-154) (average 11-fold).


CONCLUSIONS
Type-1 polarization of GM-CSF/IL-4-generated DCs enhances their ability to present allogeneic tumor cells and to induce CD8(+) T cells recognizing different PCa cells and multiple defined PCa-specific epitopes. These observations help to develop improved immunotherapies of PCa for patients with different HLA types and lacking autologous tumor material.
Wieckowski
Eva
E
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Chatta
Gurkamal S
GS
Mailliard
Robbie M
RM
Gooding
William
W
Palucka
Karolina
K
Banchereau
Jacques
J
Kalinski
Pawel
P
D000469:Alkaline Phosphatase / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D018417:Th1 Cells / Q000276:immunology
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D018664:Interleukin-12; D000469:Alkaline Phosphatase; D017430:Prostate-Specific Antigen