Research

Elucidating the role of immunoproteasome in platelet-driven immune response

Code:

J3-1745

Range:

01. July 2019 - 30. June 2023

Range:

0,65 FTE

Leader:

Martina Gobec

Field:

3.01 Medical sciences/ Microbiology and immunology

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.