o:1690 Efekti sistemske aplikacije IL-33 na progresiju mišjeg melanoma Effects of systemic IL-33 treatment on the progression of murine melanoma : doctoral dissertation sr Melanom je jedan od najagresivnijih tumora koji karakterišu povećaninvazivni i metastatski potencijal, kao i sticanje rezistencije na terapeutike. IL-33je član familije IL-1 koji reguliše urođeni i stečeni imunski odgovor. Uloga IL-33 utumoru je kompleksna i nije u potpunosti razjašnjena.Cilj studije je da se ispitaju efekti sistemske aplikacije IL-33 na progresijumišjeg melanoma, kao i na modulaciju antitumorskog imunskog odgovora.Miševima čistog soja C57BL/6 je subkutanom aplikacijom ćelija B16-F1 iB16-F10 varijeteta mišjeg melanoma transplantiran primarni melanom, dok su imeksperimentalne metastaze indukovane posle intravenske aplikacije ćelija. Nakonrazličitih modaliteta aplikacije mišjeg rekombinantnog IL-33, ispitivan je efekatIL-33 na rast i metastaziranje melanoma. Analiziran je uticaj IL-33 na modulacijuimunskog odgovora u metastaskom tkivu pluća.IL-33 suprimira rast primarnog melanoma i sa većim (B16-F10) i sa manjimmetastatskim potencijalom (B16-F1), dok s druge strane stimuliše hematogenometastaziranje B16-F1 varijeteta melanoma u pluća. Prometastatska aktivnost IL-33 seogleda u tome što redukuje citotoksički kapacitet i favorizuje imunosupresivnifenotip CD8+T limfocita u metastatskom tkivu pluća. Zabeležena je povećanaakumulacija mijeloidnih supresorskih ćelija, kao i regulatornih T limfocita.Prometastatski efekat IL-33 dodatno je potvrđen i nalazom povećane koncentracijeIL-33 u serumu obolelih od melanoma sa detektovanim regionalnim metastazama.Dobijeni nalaz ukazuje da uprkos supresivnom delovanju na rast primarnogmelanoma, IL-33 podstiče rast hematogenih metastaza i to tako što smanjujeefikasnost stečenog antitumorskog imunskog odgovora. Prometastatski efekat IL-33 umišjem melanomu dovodi u pitanje njegovu eventualnu terapijsku primenu. Melanoma is one of the most aggressive tumors, characterized by high invasiveness,metastatic potential and resistance to therapeutics. IL-33 is member of IL-1 cytokine familythat regulates both innate and acquired immune response. The role of IL-33 in tumorprogression is complex and not fully understood.The aim of the study is to evaluate effects of systemic IL-33 application on murinemelanoma progression, as well as the effects of IL-33 on modulation of antitumor immuneresponse.For the assessment of tumor growth, wild-type C57BL/6 mice were injectedsubcutaneously with B16-F1 or B16-F10 cells, whilst for experimental metastasis assays,malignant cells were injected intravenously. Using different modalities of IL-33 application,effects of the mouse recombinant IL-33 on growth and melanoma metastasis were evaluated.Effects of IL-33 on antitumor immune response in metastatic lungs were analyzed.IL-33 restricted primary tumor growth of both high metastatic (B16-F10) and lowmetastatic (B16-F1) variant, while on the opposite promoted growth of the B16-F1 melanomametastasis in the lungs. Prometastatic IL-33 activity is reflected in significant reduction ofCD8+T cells cytotoxicity and promotion of CD8+T cell immunosuppressive phenotype.There was a significant accumulation of myeloid suppressor cells and regulatory T cells in themetastatic lung. The significance of IL-33 for melanoma metastases was also documented in asignificantly increased level of serum IL-33 melanoma patients with regional metastases.These findings implicate that, despite restrictive effects on primary melanoma, IL-33promotes growth of hematogenous melanoma metastasis in mice by modulation of acquiredimmune response, thus questioning its usage in therapy of human advanced melanoma. - 91552100 133065225 91552101 8731 2024-04-19T12:20:23.053Z 45 no 46 Andra, 1986- Jevtović 71680521 2023 63 mentor Gordana, 1976- Radosavljević 13591143 2023 63 predsednik komisije Nebojša, 1958- Arsenijević 13557351 2023 63 član komisije Danilo, 1963- Vojvodić 10764647 2023 63 član komisije Ivan, 1977- Jovanović 3999847 2023 119 listova 4183330 http://phaidrakg.kg.ac.rs/o:1690 no yes 12 2024-04-19T12:20:23.320Z 70 Melanom, IL-33, metastaziranje, CD8+T limfociti Melanoma, IL-33, metastasis, CD8+T cells 616-097(043.3) 1738 34A05 2023