PGE2 is tumor-associated inflammatory mediator involved in development and regulation of tumor immune response. PGE2 affects myeloid cells, in particular it controls their accumulation as well as their functions. Tumor-associated PGE2 induces COX2/PGE2 feedback loop in myeloid precursor cells, promoting the induction and accumulation of myeloid-derived suppressor cells, MDSCs. Accumulation ensues from persistent COX2/PGE2regulated expression of immuno-suppressive factors IL10, NOS2, IDO1, ARG1, IL4Ra and CXCR4/CXCL12dependent resistence of MDSC in tumor environment. COX2/PGE2controlled suppressive factors prevent CTL immune responses. Inhibition of COX2/PGE2 feedback with COX2 inhbitor celecoxib or EP2 and EP4 antagonists prevents expression of immunosuppressive factors and CTL suppression as well as migration capacity of MDSCs in tumor environment. The results demonstrate the rationale for inhibition of COX2/PGE2 feedback loop in antitumor therapy.
B.04 Guest lecture
COBISS.SI-ID: 3079281DCSIGN is a type II Ctype lectin that functions as an adhesion molecule located on dendritic cells (DCs). It enables some of the functions of DCs, including migration, pathogen recognition, internalisation and processing, and their binding to T cells. HIV1 has been reported to enter DCs by being bound to DCSIGN, escaping the normal lytic pathway in DCs' endosomes and avoiding the immune system defence system. A very similar mechanism of survival has been observed for some other pathogens. This makes DCSIGN a receptor of interest in the design of distinctive antiinfectives that would inhibit DCSIGNpathogen interaction by blocking the very first step in pathogen infection. In this review we outline the development of DCSIGN antagonists, focusing mainly on a glycomimetic approach. Based on the fact that DCSIGN binds mannoseand fucosebased oligoand polysaccharides, their structural mimics have been designed and proved to inhibit pathogenDCSIGN interaction. Furthermore, recent in vitro studies have demonstrated that DCSIGN antagonists block effectively the transmission of pathogens like HIV1 and Ebola to CD4+ T cells. Although DCSIGN has not been validated in vivo as a druggable target yet, we await future DCSIGN antagonists as a new and highly promising group of novel antiinfectives.
B.04 Guest lecture
COBISS.SI-ID: 3130993We describe a simple and clinicallycompatible method of generating large numbers of immunosuppressive cells with the characteristics of myeloidderived suppressor cells (MDSCs) from peripheral blood precursor cells, using exogenous prostaglandin E2 (PGE2), the factor known to signal vial EP1, EP2, EP3, and EP4 receptors and to activate the adenylate cyclasetriggered cAMP/PKA/CREB signaling pathway. PGE2, EP2 and EP4 agonists (or factors enhancing their expression), mediators of their downstream signaling, or inhibitors of PGE2
F.21 Development of new health/diagnostic methods/procedures