The main goal of this project is to explore new fundamental pathways involved in the regulation of antitumor immune response. Since the immunosuppressive tumor microenvironment constitutes a key barrier to effective immunotherapy, our predominant ambition is to characterize novel, hitherto unknown metabolic changes that can support the survival of tumor cells and the escape from the immune surveillance. We have recently discovered a new metabolite within tumor microenvironment with a robust ability to inhibit the activity of immune cells and their potential to kill target tumor cells. Within the project, we plan to corroborate on our preliminary findings in order to establish the role of this factor in mitigating antitumor immune response. To this end, we will determine the level of its production within tumors in murine models. Moreover, we will relate these findings to human data by analysing the immune milieu and the expression of enzymes involved in generation of this metabolic agent in a cohort of cancer patients. We will also investigate the mechanisms by which this factor could perturb the functions of tumor-infiltrating effector cells. Finally, we aspire to use the knowledge gained during the implementation of this project to propose innovative therapeutic solutions. Specifically, we will investigate whether and how the inhibition of selected enzymes involved in the generation of this new metabolic checkpoint can impact on the efficacy of immunotherapeutic agents, including immune checkpoint inhibitors, arginase inhibitors as well as adoptive therapy with CAR-T cells and CAR-NK cells. We strongly believe that by achieving the goals of our project we will make a significant step forward in order to develop and to design cutting-edge therapeutic strategies. These compelling solutions would further improve the efficacy of tumor immunotherapy, thus contributing to a breakthrough advance in cancer treatment.

Heart Failure with preserved Ejection Fraction (HFpEF) represents a major unmet clinical need for improved diagnostics, prognostics, and development of treatments to limit the morbimortality of this increasingly common disease linked to metabolic syndrome (MetS). The objective of LYMIT-DIS is to forward our understanding of the mechanisms involved in the cardiac diastolic dysfunction in HFpEF, with the aim to identify and evaluate new tractable therapeutic targets. In this integrated, multidisciplinary and translational project, we will evaluate the impact of MetS-induced HFpEF, in a gender-dependent manner, in both experimental models and clinical cohorts. Our focus will be to address the combined role of cardiac lymphatic and blood microvascular dysfunctions in mediating key pathological steps such as cardiac blood supply/demand imbalance, edema, and inflammation, and their effects on cardiac metabolism and fibrosis. The key innovative aspects of our project are 1) investigations of the impact of MetS and gender on cardiac lymphangiogenesis, angiogenesis, and microvascular glycocalyx remodeling; and 2) evaluations of the roles of these processes in HFpEF pathogenesis. At the cellular level, we will determine how MetS alters paracrine signalling in endothelial cells, macrophages, and fibroblasts vs. cardiomyocytes in search for new molecular targets against diastolic dysfunction. Further, using cutting-edge technology, we will investigate if insufficient cardiac perfusion and lymphatic transport in MetS modulate cardiac metabolism and fibrosis thereby predisposing to HFpEF.

In 2013, the Science magazine announced Immunotherapy of cancer as the ‘Breakthrough of the Year’. The results of ongoing clinical studies with new cancer immunotherapeutics strongly support this enthusiasm. Following the lead of the top research groups, the Coordinator of the present proposal, Medical University of Warsaw (MUW) displays a predominant ambition of becoming a major player in the thriving area of Immuno-Oncology. MUW is one of the leading centres of competence in the Oncology field in Poland and presents a robust desire for further improvement of its excellence merits. Therefore, the main concept of the STREAM proposal is to bring together the high-level European research organizations with synergistic scientific and innovative expertise in the field of Immuno-Oncology, in order to establish an international, long-term, strategic partnership with MUW. The main model of the STREAM proposal is to foster enhanced scientific dialogue and twinning between MUW and four outstanding research centres via trans-national visits of scientific personnel, joint organization of a summer school and workshops, as well as promoting the active participation of STREAM researchers in the prestigious scientific conferences. Within the duration of the current project we intend to significantly enrich MUW’s, regional and national quality profile regarding all of the variables of Composite indicator of Research Excellence in the Immuno-Oncology area. We will also set a new standard for conducting bioresearch and innovative thinking in Poland. We expect that the scale, ambition, and innovative character of the proposed project will bring the MUW’s excellence to a new level - internationally recognized and competitive, in order to contribute to the well-being of the society and knowledge-based economy of Poland and EU. Our proposal provides an exceptional occasion to achieve real impact on human health, quality of life and economic status in the new area of enlarged Europe.