Projects / Programmes
Elucidating the role of immunoproteasome in platelet-driven immune response
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B500 |
Biomedical sciences |
Immunology, serology, transplantation |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
immunoproteasome, platelets, immunotherapy, breast cancer, tumor microenvironment
Researchers (12)
Organisations (2)
Abstract
The development of cancer metastasis is a disease hallmark, which predicts a poor outcome. Identifying novel therapeutic approaches that impair the immunosuppressive tumour microenvironment and enhance the immune response is of pivotal need. Herein, we propose a novel pharmacological target in shaping these processes, namely the immunoproteasome. Immunoproteasome is a multi-catalytic enzyme, which plays a key role in MHC class I antigen processing and in forming the innate and adaptive immune response through regulation of cytokine production, immune cell differentiation, survival, and proliferation. The cells of hematopoietic origin preferentially express the immunoproteasome; however, its expression can also increase in non-hematopoietic cells upon regulatory induction by inflammatory cytokines (e.g. IFN-γ, TNF-α). Recently, it was demonstrated that the smallest cells of the blood, i.e. platelets, also express an active form of the immunoproteasome. The role of platelets in the human body extends far beyond their role in haemostasis. Research revealed that they play an important part in initiating inflammation, metastasis and growth of tumour cells, lymphatic development, and atherosclerosis. In cancer spread, the role of platelets is reported on several levels (e.g. they coat tumour cells and physically protect them from NKs, several molecules secreted from platelets help to maintain an immunosuppressive tumour microenvironment, they transfer their HLA class I molecules onto the tumour cell, which leads to camouflaging them from the immune cells).
In the project, we propose a new strategy of immunotherapy - targeting the immunoproteasome to decrease the platelets’ immunosuppressive environment. Such approach has never been studied, yet it offers itself as a reasonable and intriguing strategy due to the abundance of platelets and ‘druggability’ of the pharmacological target. In regards to the malignancy the focus will be on breast cancer cells, due to high occurance. In the proposed project, we will tackle this question through three well defined objectives, in which we will (i) identify the role of immunoproteasome modulation on platelet function, (ii) delineate how the immunoproteasome modulates the immunosuppressive microenvironment for cancer cells, and (iii) determine how the modulation of the immunoproteasome shapes the interaction of platelets, tumour cells, and immune cells.
The successful implementation and completion of the project is guaranteed by the thoughtfully-structured work packages and the complementarity of expertise and experiences of the proposed consortium. The latter constitutes of members from the Faculty of pharmacy (University of Ljubljana, Slovenia), the Institute of Pharmacy (University of Bonn, Germany), and the Institute Service of Slovenia for Transfusion Medicine. With the proposed project, we intend to delineate the immunoproteasome as a target in preventing cancer spread through the disruption of the immunosuppressive tumour microenvironment.
Significance for science
Scientific quality of the project lies in the novelty of the proposed target for cancer immunotherapy, as well as in the complementary approach of conducting this project. We will investigate the role of immunoproteasome in platelets, which has not been addressed before. Moreover, we will elucidate how the modulation of the immunoproteasome shifts the crosstalk of platelets, tumour cells, and immune cells. This will contribute to the delineation of the immunoproteasome as a target in preventing cancer spread through the disruption of the immunosuppressive tumour microenvironment. Moreover, we aim to develop a flow cytometry method, which will enable simultaneous detection of individual subunits of both proteasomes in complex biological samples. This is not only valuable for this project, but is also transferable to the broader scientific community, as inhibitors of constitutive proteasome are used in clinical practice and inhibitors of immunoproteasome are already in phase 2 of clinical trials. The availability of such method will allow a faster, valuable and more detailed insight into composition of the proteasomes in targeted diseases, potentially allowing adjustment of the therapeutic treatment with marketed (immuno)proteasome inhibitors. The project research also links three research groups within Slovenia and abroad, which will contribute to the integration of Slovenian science in international research area. In the long run, we hope that new scientific concepts and findings emerging from this project will trigger additional research in a broader scientific community, which would validate our findings and potentially lead to translation into clinical practice. Moreover, the project itself can be of great value to the pharmaceutical industry in terms of drug-repurposing of some (immuno)proteasome inhibitors, which are already in clinical use or are being investigated in the phase 2 of clinical trials.
Significance for the country
Scientific quality of the project lies in the novelty of the proposed target for cancer immunotherapy, as well as in the complementary approach of conducting this project. We will investigate the role of immunoproteasome in platelets, which has not been addressed before. Moreover, we will elucidate how the modulation of the immunoproteasome shifts the crosstalk of platelets, tumour cells, and immune cells. This will contribute to the delineation of the immunoproteasome as a target in preventing cancer spread through the disruption of the immunosuppressive tumour microenvironment. Moreover, we aim to develop a flow cytometry method, which will enable simultaneous detection of individual subunits of both proteasomes in complex biological samples. This is not only valuable for this project, but is also transferable to the broader scientific community, as inhibitors of constitutive proteasome are used in clinical practice and inhibitors of immunoproteasome are already in phase 2 of clinical trials. The availability of such method will allow a faster, valuable and more detailed insight into composition of the proteasomes in targeted diseases, potentially allowing adjustment of the therapeutic treatment with marketed (immuno)proteasome inhibitors. The project research also links three research groups within Slovenia and abroad, which will contribute to the integration of Slovenian science in international research area. In the long run, we hope that new scientific concepts and findings emerging from this project will trigger additional research in a broader scientific community, which would validate our findings and potentially lead to translation into clinical practice. Moreover, the project itself can be of great value to the pharmaceutical industry in terms of drug-repurposing of some (immuno)proteasome inhibitors, which are already in clinical use or are being investigated in the phase 2 of clinical trials.
