DENDRITIC CELLS IN ANTITUMOR IMMUNE-RESPONSES .2. DENDRITIC CELLS GROWN FROM BONE-MARROW PRECURSORS, BUT NOT MATURE DC FROM TUMOR-BEARING MICE, ARE EFFECTIVE ANTIGEN CARRIERS IN THE THERAPY OF ESTABLISHED TUMORS

Antitumor CTL responses were studied in a model tumor bearing a mutant human p53 gene. We found ineffective induction of antitumor CTL in mi ce bearing these tumors associated with measurable defects in the func tion of dendritic cells (DC) from these animals, In this study we inve stigate the mechanism of this defect in mature DC and find that functi onal DC can be generated by growth from the bone marrow of tumor-beari ng animals. Tumor cell supernatants did not affect the function of mat ure DC obtained from the spleen of tumor-bearing animals, but signific antly suppressed the ability to generate functional DC from the bone m arrow of control mice in vitro. This suggests that tumor cells may rel ease factors which block early stages of DC maturation from precursors . DC generated from the bone marrow of tumor-bearing mice showed norma l potential to stimulate allogeneic T cells, to stimulate anti-mutant p53 peptide-specific cytotoxic T cells, and to induce anti-p53 CTL res ponses in vivo in control mice. Repeated immunization with peptide-pul sed DC generated from the bone marrow of control mice (every 4-5 days) blocked progression of established tumors. Immunization of mice with peptide-pulsed DC obtained from the spleen of tumor-bearing mice (4 we eks after tumor injection) did not affect the tumor growth, whereas im munization with peptide-pulsed DC generated from bone marrow of tumor- bearing mice resulted in significantly prolonged survival and delayed tumor growth. Tumor progression was associated with change of the bala nce Th1/Th2 cells in favor of the Th2-like cytokine profile, while eff ective immunization was associated with a shift to the Th1 phenotype. Thus, frequent immunization of mice with mutant p53 peptide-pulsed DC generated from stem cells of tumor-bearing hosts can induce effective antitumor CTL responses associated with production of Th1 cells and le ad to significant antitumor effects. (C) 1996 Academic Press, Inc.