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/PGE2-regulated expression of immunosuppressive factors IL10, NOS2, IDO1, ARG1, IL4Ra and CXCR4/CXCL12-dependent 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: 3079281DC-SIGN is a type II C-type 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. HIV-1 has been reported to enter DCs by being bound to DC-SIGN, 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 DC-SIGN a receptor of interest in the design of distinctive anti-infectives that would inhibit DC-SIGN-pathogen interaction by blocking the very first step in pathogen infection. In this review we outline the development of DC-SIGN antagonists, focusing mainly on a glycomimetic approach. Based on the fact that DC-SIGN binds mannose- and fucose-based oligo- and polysaccharides, their structural mimics have been designed and proved to inhibit pathogen-DC-SIGN interaction. Furthermore, recent in vitro studies have demonstrated that DC-SIGN antagonists block effectively the transmission of pathogens like HIV-1 and Ebola to CD4+ T cells. Although DC-SIGN has not been validated in vivo as a druggable target yet, we await future DC-SIGN antagonists as a new and highly promising group of novel anti-infectives.
B.04 Guest lecture
COBISS.SI-ID: 3130993We describe a simple and clinically-compatible method of generating large numbers of immunosuppressive cells with the characteristics of myeloid-derived 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 cyclase-triggered cAMP/PKA/CREB signaling pathway. PGE2, EP2 and EP4 agonists (or factors enhancing their expression), mediators of their downstream signaling, or inhibitors of PGE2 degradation can be used to generate large numbers of MDSCs for the immunotherapy of autoimmune diseases, spontaneous and specific pathogen-induced inflammatory diseases (including some infectious diseases), development of premalignant and malignant lesions, for certain forms of infertility, to accelerate wound healing, and for prevention and treatment of transplant rejection.
F.21 Development of new health/diagnostic methods/procedures