Chemosensitization of pancreatic carcinoma cells to enhance T cell-mediated cytotoxicity induced by tumor lysate-pulsed dendritic cells.
Dendritic cells (DCs) can induce cytotoxic T-cell (CTL) responses against tumor antigens in vitro and in vivo, yet few cancer patients experience tumor regression after DC-based vaccination. Combination with other treatment modalities, such as radiation or pharmacologic anticancer agents, may reduce tumor cell resistance against immune responses. The authors tested whether treatment with gemcitabine or cyclooxygenase-2 (COX-2) inhibitors increases the sensitivity of pancreatic carcinoma cells to CTL-mediated killing. Monocyte-derived DCs of HLA-A2+ donors were loaded with lysate from the HLA-A2+ pancreatic carcinoma cell line Panc-1 and co-cultured with autologous CD3+ T cells. ELISPOT and cytotoxicity assays performed after two rounds of in vitro stimulation confirmed induction of a tumor-specific CTL response. Changes in the magnitude and the effector mechanism of the CTL response were analyzed after treatment of Panc-1 cells with gemcitabine and COX-2 inhibitors. Compared with gemcitabine, COX-2 inhibitors more effectively sensitized Panc-1 cells to CTL-mediated killing and showed less inhibition of T-cell activation by DCs in vitro. Using anti-CD95 blocking antibody, the authors showed that the increase in CTL-mediated tumor cell killing observed after treatment with COX-2 inhibitors is dependent on CD95/CD95 ligand interaction. Increased apoptosis of Panc-1 cells treated with COX-2 inhibitor was also observed after incubation with agonistic anti-CD95 antibody. Sensitization of cancer cells to CD95-dependent killing by CTLs represents a novel mechanism of action for COX-2 inhibitors and provides a rationale for their concomitant use with immunotherapeutic strategies such as DC-based vaccination.
Section of Gastroenterology, Medizinische Klinik Innenstadt, University of Munich, 80336 Munich, Germany.
Marc
M
Dauer
Jan
J
Herten
Christian
C
Bauer
Frederik
F
Renner
Katharina
K
Schad
Max
M
Schnurr
Stefan
S
Endres
Andreas
A
Eigler
D000951:Antigens, Neoplasm / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D019014:fas Receptor / Q000276:immunology; D000093542:Gemcitabine
D000951:Antigens, Neoplasm; D016207:Cytokines; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D019014:fas Receptor; D003841:Deoxycytidine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000093542:Gemcitabine