title: Adaptive Resistance to Immunotherapy Directed Against p53 Can be Overcome by Global Expression of Tumor-Antigens in Dendritic Cells.
abstract: Immunotherapy of cancer utilizes dendritic cells (DCs) for antigen presentation and the induction of tumor-specific immune responses. However, the therapeutic induction of anti-tumor immunity is limited by tumor escape mechanisms. In this study, immortalized dendritic D2SC/1 cells were transduced with a mutated version of the p53 tumor suppressor gene, p53M234I, or p53C132F/E168G, which are overexpressed in MethA fibrosarcoma tumor cells. In addition, D2SC/1 cells were fused with MethA tumor cells to generate a vaccine that potentially expresses a large repertoire of tumor-antigens. Cellular vaccines were transplanted onto Balb/c mice and MethA tumor growth and anti-tumor immune responses were examined in vaccinated animals. D2SC/1-p53M234I and D2SC/1-p53C132F/E168G cells induced strong therapeutic and protective MethA tumor immunity upon transplantation in Balb/c mice. However, in a fraction of immunized mice MethA tumor growth resumed after an extended latency period. Analysis of these tumors indicated loss of p53 expression. Mice, pre-treated with fusion hybrids generated from D2SC/1 and MethA tumor cells, suppressed MethA tumor growth and averted adaptive immune escape. Polyclonal B-cell responses directed against various MethA tumor proteins could be detected in the sera of D2SC/1-MethA inoculated mice. Athymic nude mice and Balb/c mice depleted of CD4(+) or CD8(+) T-cells were not protected against MethA tumor cell growth after immunization with D2SC/1-MethA hybrids. Our results highlight a potential drawback of cancer immunotherapy by demonstrating that the induction of a specific anti-tumor response favors the acquisition of tumor phenotypes promoting immune evasion. In contrast, the application of DC/tumor cell fusion hybrids prevents adaptive immune escape by a T-cell dependent mechanism and provides a simple strategy for personalized anti-cancer treatment without the need of selectively priming the host immune system.
authors.affiliation: Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University of Freiburg , Freiburg , Germany.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Humar
authors.affiliation: Internistische Onkologie, Tumor Biology Center , Freiburg , Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Azemar
authors.affiliation: Basilea Pharmaceutica International Ltd. , Basel , Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Institute for Biomedical Research, Georg Speyer Haus , Frankfurt am Main , Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Groner
keywords: CD8+ T-cell mediated tumor suppression; adaptive immune escape; dendritic cell–tumor cell fusion; immune surveillance of cancer; tumor-specific antigen expressing dendritic cells