Projects / Programmes
Cancer immunotherapy modulation by ultrasound
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
sonogenetics, ultrasound, cancer immunotherapy, transcriptional regulatiom, ion channels, protein based gas vesicles
Researchers (18)
Organisations (2)
Abstract
Immunotherapy has great potential to treat cancer based on activation of the immune system to recognize and kill cancer cells. The evasion of immune recognition by the selection or suppression of cancer cell expressing T cell targets and the immunosuppressive tumor microenvironment (TME) may lead to a failure of immunotherapy. Therefore, there is a need for advanced therapeutic strategies enabling modulation of TME in combination with strengthening of tumor specific engineered Teff cells with precise spatial and temporal control of therapy within the solid tumors to avoid systemic adverse effects. Optogenetic tools revolutionized life sciences by developing genetically encoded tools for manipulation of the cellular response to light as the spatially and temporally precisely defined signal. However translation of optogenetics to therapy has been hindered due to the weak light penetration through the tissue. An appropriate alternative to light may be provided by the ultrasound (US), which can also be precisely programmed and focused, and in contrast to light it can penetrate deep into tissues, potentially enabling remote control of cells with exciting possibilities for medical and biotechnological application.
The goal of this proposal is to develop the potential of US as a noninvasive and specific trigger for activation of target cells and induction of the transcriptional regulation of the selected genes in vivo by US stimulation. In short, we aim to construct the genetic tools to enhance sensitivity of cells to US, and to couple mechanoreceptor activation to the transcription of selected genes.
1. Enhance mechanosensing of mammalian cells to stimulation by US
We propose to enhance the response of immune cells to US by the ectopic expression of mechanosensitive ion channels and their fusion with the cytoskeleton and/or extracellular matrix interacting domains. Furthermore, the protein-based gas vesicles and/or lipid microbubbles attached to cell membrane will be used to further enhance the US stimulation of target cells.
2. Coupling of mechanosensing receptor activation to the transcriptional activation mediated by designed Ca-responsive transcription factors
Mechanosensing will be coupled to activation of selected cellular signaling pathways that will be tested in several cell types. We plan to couple calcium influx to the transcriptional activation though the engineered NFAT (nuclear factor of activated T-cells) transcription factor. Nuclear translocation of NFAT is activated by a calcium dependent dephosphorylation and will be used to target endogenous and ectopic genes. Additionally, Ca2+-inducible transcription regulators will be modified to target the desired genes by the replacement of the DNA targeting sequence with designed Transcription activator-like effector (TALE) domains.
3. Implementation of in vivo US activation in the medically relevant setting
After US-induced transcriptional activation of the selected gene has been confirmed in cultured cells the next step will be to establish US activation of cells in vivo, which will provide the foundation for the therapeutic applications of sonogenetics. US-delivered acoustic stress and sonogentic cellular device will be tested for modulation of TME in the solid tumor mouse models.
The proposed project represents a highly original concept following the similar pathway as optogenetics and combines project team’s expertise in synthetic biology, cell biology, immunology, and oncology, aimed to establish a new technological platform. The project will provide an important advance on the construction of the US-responsive cellular devices that could have impact on medicine and is expected to open many avenues for the further translational research towards therapeutic application. The proven track record and expertise of the team, and preliminary results solving key issues of the proposal provide a solid foundation for the successful accomplishment of this ambitious projec
Significance for science
Despite growing knowledge on molecular mechanisms underlying common diseases we are still unable to successfully fight many of them. Cancer is the second leading cause of death globally, and was responsible for 1.3 million deaths in EU28 2014. (http://ec.europa.eu/eurostat/statistics-explained/index.php/Cancer_statistics). Consequently, the economic impact of cancer is significant and is increasing; therefore, novel therapeutic approaches integrating immunotherapy and cancer drugs combating cancer are of high relevance. Within this project we will explore and develop the potential of the ultrasound as a noninvasive approach for precisely defined cellular activation in the deep tissue and transcriptional regulation of target genes for which we will construct genetically encoded sensors, reporters and transcriptional modulators and test them in different mammalian cells as well as in in vivo studies using melanoma mouse model.
The proposed approach represents a highly innovative concept, which builds on the cutting edge optogenetics and our expertise in synthetic biology to construct a new technological platform. Sonogenetics has even greater translation potential than optogenetics due to the demonstrated lack of negative adverse effects in diagnostic ultrasound and primarily due to its noninvasiveness, which is probably the most important obstacle to wider therapeutic applications of optogenetics in neurological diseases.
The proposed project will provide an important advance on the construction of ultrasound-responsive molecular devices which have many possible implications e.g. in cancer immunotherapy, treatment of neurologic and metabolic diseases. Several ultrasound and mechanical stimulus-responsive modulators and reporters will be developed within the proposed project, which could be used as the research and therapeutic tools. One of the important advantages of the proposed direction of research is that it opens many possible avenues for the further research, such as e.g. coupling mechanoreceptor activation to the existing or designed signaling pathways, local release of imuno- and neuro- modulators and hormones, design of new cellular sensors, selection of target cells, in situ diagnostics of shear flow in endothelial cells etc.
Our interdisciplinary approach combining the expertise from synthetic and cell biology, immunology to oncology represents an innovative and original contribution in these very competitive disciplines and might open new therapeutic possibilities in a variety of diseases. The interdisciplinary nature of the project opens new possibilities for international cooperation with researchers e.g. within Horizon2020 or ERANET and bilateral projects (some listed in Section 9.2) and will recruit new PhD and undergraduate students.
Significance for the country
Despite growing knowledge on molecular mechanisms underlying common diseases we are still unable to successfully fight many of them. Cancer is the second leading cause of death globally, and was responsible for 1.3 million deaths in EU28 2014. (http://ec.europa.eu/eurostat/statistics-explained/index.php/Cancer_statistics). Consequently, the economic impact of cancer is significant and is increasing; therefore, novel therapeutic approaches integrating immunotherapy and cancer drugs combating cancer are of high relevance. Within this project we will explore and develop the potential of the ultrasound as a noninvasive approach for precisely defined cellular activation in the deep tissue and transcriptional regulation of target genes for which we will construct genetically encoded sensors, reporters and transcriptional modulators and test them in different mammalian cells as well as in in vivo studies using melanoma mouse model.
The proposed approach represents a highly innovative concept, which builds on the cutting edge optogenetics and our expertise in synthetic biology to construct a new technological platform. Sonogenetics has even greater translation potential than optogenetics due to the demonstrated lack of negative adverse effects in diagnostic ultrasound and primarily due to its noninvasiveness, which is probably the most important obstacle to wider therapeutic applications of optogenetics in neurological diseases.
The proposed project will provide an important advance on the construction of ultrasound-responsive molecular devices which have many possible implications e.g. in cancer immunotherapy, treatment of neurologic and metabolic diseases. Several ultrasound and mechanical stimulus-responsive modulators and reporters will be developed within the proposed project, which could be used as the research and therapeutic tools. One of the important advantages of the proposed direction of research is that it opens many possible avenues for the further research, such as e.g. coupling mechanoreceptor activation to the existing or designed signaling pathways, local release of imuno- and neuro- modulators and hormones, design of new cellular sensors, selection of target cells, in situ diagnostics of shear flow in endothelial cells etc.
Our interdisciplinary approach combining the expertise from synthetic and cell biology, immunology to oncology represents an innovative and original contribution in these very competitive disciplines and might open new therapeutic possibilities in a variety of diseases. The interdisciplinary nature of the project opens new possibilities for international cooperation with researchers e.g. within Horizon2020 or ERANET and bilateral projects (some listed in Section 9.2) and will recruit new PhD and undergraduate students.
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
