Efficient antitumor immunity derived from maturation of dendritic cells that had phagocytosed apoptotic/necrotic tumor cells

Dendritic cells (DCs) that acquired antigen from apoptotic tumor cells are able to induce major histocompatibility complex (MHC) class I-restricted cy totoxic T lymphocytes and antitumor immunity. In the present study, we inve stigated the efficiency of antitumor immunity derived from DCs that had pha gocytosed apoptotic/necrotic BL6-10 melanoma cells compared with that of DC s pulsed with the tumor mTRP2 peptide. Our data showed that phagocytosis of apoptotic/necrotic tumor cells resulted in maturation of DCs with up-regul ated expression of proinflammatory cytokines [interleukin (IL)-1 beta, IL-6 , tumor necrosis factor-alpha, interferon-gamma and granulocyte-macrophage colony-stimulating factor], chemokines (MIP-1 alpha, MIP-1 beta and MIP-2), the CC chemokine receptor CCR7 and the cell surface molecules (MHC class I I. CD11b, CD40 and CD86), and down-regulated expression of the CC chemokine receptors CCR2 and CCR5, These mature DCs displayed enhanced migration tow ard the CC chemokine MIP-3 beta in a chemotaxis assay in vitro and to the r egional lymph nodes in an animal model in vivo. Our data also showed that v accination with DCs that had phagocytosed apoptotic/necrotic BL6-10 cells w as able to (i) more strongly stimulate allogeneic T-cell proliferation in v itro, (ii) induce an in vivo Th I-type immune response leading to more effi cient tumor-specific cytotoxic CD8(+) T-cell-mediated immunity and (iii) er adicate lung metastases in all 6 vaccinated mice compared with mice vaccina ted with DCs pulsed with the tumor mTRP2 peptide, in which lung metastases were reduced (mean number of 16 per mouse) but not completely eradicated. T herefore, DCs that had phagocytosed apoptotic/necrotic tumor cells appear t o offer new strategies in DC cancer vaccines. (C) 2001 Wiley-Liss, Inc.