Efekti sistemske aplikacije IL-33 na progresiju mišjeg melanoma
Effects of systemic IL-33 treatment on the progression of murine melanoma
Докторанд
Jevtović, AndraМентор
Radosavljević, GordanaЧланови комисије
Arsenijević, NebojšaVojvodić, Danilo
Jovanović, Ivan
Метаподаци
Приказ свих података о дисертацијиСажетак
Melanom je jedan od najagresivnijih tumora koji karakterišu povećan
invazivni i metastatski potencijal, kao i sticanje rezistencije na terapeutike. IL-33
je član familije IL-1 koji reguliše urođeni i stečeni imunski odgovor. Uloga IL-33 u
tumoru je kompleksna i nije u potpunosti razjašnjena.
Cilj studije je da se ispitaju efekti sistemske aplikacije IL-33 na progresiju
mišjeg melanoma, kao i na modulaciju antitumorskog imunskog odgovora.
Miševima čistog soja C57BL/6 je subkutanom aplikacijom ćelija B16-F1 i
B16-F10 varijeteta mišjeg melanoma transplantiran primarni melanom, dok su im
eksperimentalne metastaze indukovane posle intravenske aplikacije ćelija. Nakon
različitih modaliteta aplikacije mišjeg rekombinantnog IL-33, ispitivan je efekat
IL-33 na rast i metastaziranje melanoma. Analiziran je uticaj IL-33 na modulaciju
imunskog odgovora u metastaskom tkivu pluća.
IL-33 suprimira rast primarnog melanoma i sa većim (B16-F10) i sa manjim
metastatskim potencijalom (B16-F1), dok s druge... strane stimuliše hematogeno
metastaziranje B16-F1 varijeteta melanoma u pluća. Prometastatska aktivnost IL-33 se
ogleda u tome što redukuje citotoksički kapacitet i favorizuje imunosupresivni
fenotip CD8+
T limfocita u metastatskom tkivu pluća. Zabeležena je povećana
akumulacija mijeloidnih supresorskih ćelija, kao i regulatornih T limfocita.
Prometastatski efekat IL-33 dodatno je potvrđen i nalazom povećane koncentracije
IL-33 u serumu obolelih od melanoma sa detektovanim regionalnim metastazama.
Dobijeni nalaz ukazuje da uprkos supresivnom delovanju na rast primarnog
melanoma, IL-33 podstiče rast hematogenih metastaza i to tako što smanjuje
efikasnost stečenog antitumorskog imunskog odgovora. Prometastatski efekat IL-33 u
mišjem 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 family
that regulates both innate and acquired immune response. The role of IL-33 in tumor
progression is complex and not fully understood.
The aim of the study is to evaluate effects of systemic IL-33 application on murine
melanoma progression, as well as the effects of IL-33 on modulation of antitumor immune
response.
For the assessment of tumor growth, wild-type C57BL/6 mice were injected
subcutaneously 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 low
meta...static (B16-F1) variant, while on the opposite promoted growth of the B16-F1 melanoma
metastasis in the lungs. Prometastatic IL-33 activity is reflected in significant reduction of
CD8+
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 the
metastatic lung. The significance of IL-33 for melanoma metastases was also documented in a
significantly increased level of serum IL-33 melanoma patients with regional metastases.
These findings implicate that, despite restrictive effects on primary melanoma, IL-33
promotes growth of hematogenous melanoma metastasis in mice by modulation of acquired
immune response, thus questioning its usage in therapy of human advanced melanoma.