Antitumor DNA vaccination against the Sox2 transcription factor
Ingrid Polakova1, Martina Duskova1, Michal Smahel1
1Department of Experimental Virology, Institute of Hematology and Blood Transfusion, 128 20 Prague 2, Czech Republic.
Abstract:
As cancer stem cells (CSCs) are resistant to chemotherapy, radiotherapy and targeted molecular therapy, immunotherapy of tumors could be aimed at their elimination. Markers specific for CSCs have not been identified to date, but microarray analyses have shown that CSCs and embryonic stem cells use similar transcriptional programs, thus suggesting the production of shared transcription factors. In this study, we developed an experimental DNA vaccine against the transcription factor Sox2 that is important for self-renewal of stem cells and is overexpressed in numerous human cancers. The Sox2 gene was codon optimized for the expression in human cells, its sequences encoding two nuclear localization signals (NLSs) were mutagenized, and the sequence coding for the PADRE helper epitope was fused with its 5' terminus. While codon optimization did not increase Sox2 production and mutagenesis in NLSs only partially reduced nuclear localization of Sox2, the addition of the PADRE epitope was crucial for the enhancement of Sox2 immunogenicity. The antitumor effect was shown after immunization against mouse oncogenic TC-1/B7 cells derived from the lung cancer cell line TC-1 and characterized by high Sox2 production. Sox2-specific reactivity in an ELISPOT assay was further augmented by the depletion of regulatory T (Treg) cells, but this depletion did not enhance the antitumor effect. These data demonstrated the induction of immune responses against the Sox2 self-antigen, but did not confirm the usefulness of Treg depletion when combined with antitumor vaccination.
Insights
This study developed a DNA vaccine targeting Sox2, a protein overexpressed in many cancers. The vaccine showed potential for cancer immunotherapy by inducing immune responses against cancer stem cells.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cancer stem cells (CSCs) exhibit resistance to conventional therapies.
- CSCs and embryonic stem cells share transcriptional programs, suggesting common targets like transcription factors.
- Sox2 is a key transcription factor for stem cell self-renewal and is overexpressed in various human cancers.
Purpose of the Study:
- To develop an experimental DNA vaccine targeting the transcription factor Sox2 for cancer immunotherapy.
- To evaluate the immunogenicity and antitumor efficacy of the Sox2 DNA vaccine.
- To investigate the role of regulatory T (Treg) cells in the vaccine's efficacy.
Main Methods:
- Codon optimization of the Sox2 gene for human expression.
- Mutagenesis of nuclear localization signals (NLSs) in Sox2.
- Fusion of the PADRE helper epitope to the Sox2 gene.
- Immunization of mice with the engineered Sox2 DNA vaccine against TC-1/B7 cancer cells.
- Assessment of Sox2-specific immune responses using ELISPOT assay.
- Evaluation of antitumor effects and the impact of Treg cell depletion.
Main Results:
- Codon optimization did not significantly increase Sox2 production.
- NLS mutagenesis partially reduced Sox2 nuclear localization.
- The addition of the PADRE epitope was critical for enhancing Sox2 immunogenicity.
- The Sox2 DNA vaccine induced Sox2-specific immune responses and demonstrated antitumor effects in a mouse cancer model.
- Sox2-specific reactivity was augmented by Treg cell depletion, but this did not improve the overall antitumor effect.
Conclusions:
- The developed DNA vaccine successfully induced immune responses against the Sox2 self-antigen.
- The PADRE epitope significantly enhanced the immunogenicity of the Sox2 vaccine.
- Treg cell depletion, while increasing Sox2-specific reactivity, did not enhance the vaccine's antitumor efficacy in this model.
- Further research is needed to confirm the therapeutic potential of Sox2-targeted immunotherapy and the role of Treg modulation.
Related Concept Videos
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:27Tumor Immunotherapy
01:30Cancer Vaccines
Cancer vaccines come in two categories: preventive (prophylactic) and treatment (active). Preventive vaccines, such as the Human Papillomavirus (HPV) vaccine, protect against viruses that cause certain...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
02:23Abnormal Proliferation