Drug- and cell-mediated antitumor cytotoxicities modulate cross-presentation of tumor antigens by myeloid dendritic cells.
The way a tumor cell dies is believed to influence both its engulfment by dendritic cells (DC) and access of the relevant antigen(s) to the cross-presentation pathway. Here we have studied the effect of lymphokine activated killer (LAK) cells, gamma-radiation and the antimetabolite drug 5-fluorouracil (5-FU) on tumor uptake by HLA-matched DC, and DC presentation of tumor antigens to autologous T lymphocytes. LAK cells and radiation were the best inducers of apoptotic death (Annexin-V+/propidium iodide-) on the gastric cell line KATO III and a primary gastric carcinoma, respectively. The highest rate of tumor uptake by monocyte-derived, granulocyte macrophage colony stimulating factor/interleukin (IL)-4-driven DC was associated with 5-FU, followed by radiation. These treatments also induced high levels of heat shock protein (hsp70). In contrast, only DC that had been taken up 5-FU- or LAK-treated tumors up-modulated IL-12 and presented tumor-associated antigens with increased efficiency, as shown by class I MHC-restricted interferon-gamma release and cytotoxic responses by autologous lymphocytes. Together, these data indicate that apoptotic death induced by anti-cancer therapies can induce distinct patterns of class I MHC cross-presentation of gastric carcinoma-associated antigens to cytotoxic T lymphocyte precursors.
Department of Oncology, Centro OncoEmatologicoSubalpino (COES), University of Turin, Italy.
Alessandra
A
Galetto
Stefano
S
Buttiglieri
Sarah
S
Forno
Francesco
F
Moro
Antonio
A
Mussa
Lina
L
Matera
D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D000951:Antigens, Neoplasm / Q000276:immunology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D005472:Fluorouracil / Q000494:pharmacology; D005720:Gamma Rays; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D015395:Histocompatibility Antigens Class I; D005472:Fluorouracil