TY  - JOUR
A1  - Humar, Matjaz
A1  - Azemar, Marc
A1  - Maurer, Martina
A1  - Groner, Bernd
T1  - Adaptive resistance to immunotherapy directed against p53 can be overcome by global expression of tumor-antigens in dendritic cells
T2  - Frontiers in oncology
N2  - 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.
KW  - immune surveillance of cancer
KW  - tumor-specific antigen expressing dendritic cells
KW  - adaptive immune escape
KW  - dendritic cell–tumor cell fusion
KW  - CD8+ T-cell mediated tumor suppression
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/35402
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-354026
SN  - 2234-943X
N1  - Copyright © 2014 Humar, Azemar, Maurer and Groner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
VL  - 4
IS  - 270
PB  - Frontiers Media
CY  - Lausanne
ER  -