Projects / Programmes
Improvement of immunotherapeutic potential of NK cells through modulation of cystatin F
| Code |
Science |
Field |
Subfield |
| 4.06.00 |
Biotechnical sciences |
Biotechnology |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.04 |
Medical and Health Sciences |
Medical biotechnology |
Cystatin F; NK cells; Immunotherapy; Cancer; Peptidases
Researchers (21)
Organisations (3)
Abstract
The effectiveness of conventional therapeutic modalities, including chemotherapy and radiotherapy, is limited due to drug resistance acquired by tumor cells during systemic treatment. Moreover, convenient antitumor drugs are practically ineffective against cancer stem cells, which represent a dormant pool of cells able to induce tumor recurrence. Cancer immunotherapy may overcome several limitations of conventional treatment regarding triggering drug resistance. Several types of immunotherapy have so far been tested in clinical studies, among them the use of tumor cell-directed monoclonal antibodies, and those acting as immune checkpoint inhibitors achieved the greatest success. Cell-based immunotherapy, which employs the application of autologous or allogeneic tumor specific T cells and NK cells into patients, is less established, however, the results of clinical studies are promising. The advantage of NK cell based immunotherapy in comparison to T cells is that NK cells can lyse tumor cells that are “invisible” to T-cells, including cancer stem cells. They can also promote the transition of tumor stem cells to differentiated tumor cells which are more sensitive for T cells and for conventional treatment. The main obstacle limiting the therapeutic use of NK cells is the loss of their cytotoxicity during the expansion and treatment. This project provides an innovative approach how to improve NK cell cytotoxicity by regulation of cystatin F, which is an important signaling molecule tumor cells utilize to induce immune suppression. Specific properties, such as transcriptional factor, dimeric protein, activation peptidase, glycosylation and transport to endo/lysosomal vesicles, which distinguish cystatin F from other related peptidase inhibitors, guarantee selective targeting of immunosupressive processes in cytotoxic cells with negligible off-target effects. By exploring various methods, developed and applied in this project to impair cystatin F function, such as gene silencing and knock out, inhibition of cystatin F activating peptidase and modulation of glycosylation, we will be able to enhance/prolong the cytotoxicity of NK cells. Long-term cytotoxic NK cells would be more effective for cancer treatment and consequently better outcome for cancer patients is expected.
Significance for science
Cancer is the second leading cause of death in the developed world. It affects predominantly older population and due to the prolonged lifetime its incidence is highly increasing. Today cancer represents not only a health problem but also a big social and financial burden for the society. The success of conventional therapeutics is limited and to control the disease, new approaches tailored for individual patients are urgently needed. Immunotherapy provided a significant step towards more effective eradication of malignant tumors, which were considered as incurable with conventional chemo- and radiotherapeutics. Besides targeting tumor antigens new generations of immunotherapeutics are focused on inactivation of various immune check point molecules, suppressing antigen presentation and activation of T cell receptors, as well as on activation and propagation of effector immune cells, such as NK cells and T cells which recognize and kill specifically tumor cells. These processes involve an active role of peptidases and their inhibitors and to understand their functions is a prerequisite for further improvements towards better patient's anti-tumor immune response and to overcome the mechanisms of immune suppression. Targeting cystatin F, a negative regulator of NK cell cytotoxic machinery as proposed within this project will enable clinicians to obtain a therapeutically sufficient number of highly cytotoxic NK cells which would be less susceptible to immunosuppressive tumor environment and being able to effectively eradicate tumors insensitive for chemo and radiotherapy. Our results can be translated to the ongoing clinical trials on super-charged NK cells and NK-92 cells and may contribute to their better overall outcome. Moreover, they can be used for development of new biomedical products, which could be interesting for pharmaceutical and biotechnological companies or to serve as a basis for establishment of new start-up companies. The results of this project will also facilitate our collaboration with other research groups increasing the opportunities for obtaining new research funds. The implementation of the proposed project will also provide opportunities for pre-graduate and doctoral training of students in the fields of pharmaceutical biochemistry, biotechnology, immunology and tumor biology.
Significance for the country
Cancer is the second leading cause of death in the developed world. It affects predominantly older population and due to the prolonged lifetime its incidence is highly increasing. Today cancer represents not only a health problem but also a big social and financial burden for the society. The success of conventional therapeutics is limited and to control the disease, new approaches tailored for individual patients are urgently needed. Immunotherapy provided a significant step towards more effective eradication of malignant tumors, which were considered as incurable with conventional chemo- and radiotherapeutics. Besides targeting tumor antigens new generations of immunotherapeutics are focused on inactivation of various immune check point molecules, suppressing antigen presentation and activation of T cell receptors, as well as on activation and propagation of effector immune cells, such as NK cells and T cells which recognize and kill specifically tumor cells. These processes involve an active role of peptidases and their inhibitors and to understand their functions is a prerequisite for further improvements towards better patient's anti-tumor immune response and to overcome the mechanisms of immune suppression. Targeting cystatin F, a negative regulator of NK cell cytotoxic machinery as proposed within this project will enable clinicians to obtain a therapeutically sufficient number of highly cytotoxic NK cells which would be less susceptible to immunosuppressive tumor environment and being able to effectively eradicate tumors insensitive for chemo and radiotherapy. Our results can be translated to the ongoing clinical trials on super-charged NK cells and NK-92 cells and may contribute to their better overall outcome. Moreover, they can be used for development of new biomedical products, which could be interesting for pharmaceutical and biotechnological companies or to serve as a basis for establishment of new start-up companies. The results of this project will also facilitate our collaboration with other research groups increasing the opportunities for obtaining new research funds. The implementation of the proposed project will also provide opportunities for pre-graduate and doctoral training of students in the fields of pharmaceutical biochemistry, biotechnology, immunology and tumor biology.
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
