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Published on: January 6, 2014
Characterization of cell lines derived from tumors induced by TC-1 cells in mice preimmunized against HPV16 E7
Michal Smahel1, Jana Smahelová, Pavla Tejklová
1Department of Experimental Virology, Institute of Hematology and Blood Transfusion, 128 20 Prague 2, Czech Republic. smahel@uhkt.cz
Abstract:
Escape of tumor cells from the host immune system is probably the most difficult obstacle to overcome in attempts to enhance the efficacy of immunotherapy of tumors. To solve the problem, animal models with escape mechanisms found in human tumors are needed. We have already established cell lines with substantially reduced expression of MHC class I molecules that were derived from oncogenic TC-1 cells producing E6 and E7 oncoproteins of HPV16. In this study, we prepared other cell lines from TC-1-induced tumors formed infrequently in mice immunized against the E7 antigen. These clones differed in morphology and both in vitro and in vivo growth properties. After vaccination with the highly efficient anti-E7 DNA vaccine several clones appeared to be quite resistant to induced anti-tumor immunity. Detection of the production of the MHC class I molecules and B7.1 costimulatory molecule did not provide clues to understand the mechanism of immunoresistance of the clones. Therefore, we performed transcriptional profiling using Atlas Mouse Cancer 1.2 Array (BD Clontech). Among the genes differently expressed in the examined cell lines were those of three cytokines influencing immune cells: MCP-1, osteopontin, and midkine. Altered secretion of MCP-1 chemokine was verified by ELISA. In addition, expression of the E7 oncogene was reduced in all TC-1 clones. Most importantly, one of anchor amino acids in the immunodominant epitope of E7 was mutated in all immunoresistant clones. Such mutations of HPV oncogenes must be considered in therapeutic-vaccine development and evaluation.
Insights
Tumor cells evade immune responses, hindering cancer immunotherapy. Researchers identified mutations in the E7 oncogene within resistant tumor cell lines, crucial for developing effective therapeutic vaccines against HPV-induced cancers.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Tumor cell immune escape is a major challenge in cancer immunotherapy.
- Human Papillomavirus (HPV) oncoproteins E6 and E7 drive tumor development.
- Developing animal models that mimic human tumor immune evasion is critical.
Purpose of the Study:
- To investigate mechanisms of tumor cell immune resistance in a mouse model.
- To identify genetic alterations contributing to immunotherapy resistance.
- To inform the development of therapeutic vaccines against HPV-associated cancers.
Main Methods:
- Generation of HPV16 E7-expressing TC-1 tumor cell lines.
- Induction of tumors and subsequent immunization with an anti-E7 DNA vaccine.
- Transcriptional profiling using Atlas Mouse Cancer 1.2 Array.
- Analysis of MHC class I, B7.1, cytokine expression, and E7 oncogene mutations.
Main Results:
- Several TC-1 tumor cell clones exhibited resistance to anti-tumor immunity after vaccination.
- Differential gene expression revealed altered levels of MCP-1, osteopontin, and midkine.
- Reduced E7 oncogene expression and mutations in the immunodominant E7 epitope were observed in resistant clones.
Conclusions:
- Mutations in HPV oncogenes, specifically the E7 epitope, can lead to tumor cell immune resistance.
- These findings highlight the importance of considering oncogene mutations in therapeutic vaccine design and evaluation.
- Understanding these escape mechanisms is vital for improving cancer immunotherapy efficacy.
