Drug- and cell-mediated antitumor cytotoxicities modulate cross-presentation of tumor antigens by myeloid dendritic cells

Abstract

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.